118 6 Diseases of the Brain and Meninges

10/1/79		11/1/79		2/11/80		3/28/80

50 µV

1 s

Tc 0.3

EKG

Fig. 6.30 The progression of EEG changes over time in Creutzfeldt−Jakob disease. The diagnosis of CJD in this 57-year-old woman was later confirmed by autopsy. 6 weeks after the onset of

vacuolization and the formation of amyloid plaques (spongiform encephalopathy, SEP). The main prion diseases are Creutzfeldt−Jakob disease, kuru, Gerstmann− Sträussler−Scheinker syndrome, familial progressive subcortical gliosis, and familial fatal insomnia.

Creutzfeldt−Jakob disease , the most common prion disease in Europe and North America, is nevertheless rare, with an incidence of about one case per million individuals per year. It presents initially with mental abnormalities, insomnia, and fatigability. Soon, progressive dementia develops, along with pyramidal tract signs, cerebellar signs, abnormalities of muscle tone, fasciculations, and myoclonus. In about two-thirds of patients, the EEG reveals characteristic, periodic triphasic and tetraphasic theta and delta waves (Fig. 6.30). The disease progresses rapidly, leading to a decorticate state and death within months of onset. A variant of Creutzfeldt− Jakob disease has attracted considerable attention in the past decade, particularly in the United Kingdom, because it is contracted by eating beef derived from cows with bovine spongiform encephalopathy (BSE, “mad cow disease”).

Slow virus diseases

The slow virus diseases are characterized by extremely long incubation periods, a protracted, chronically progressive course, and little or no response to treatment. SSPE is the most common slow virus disease.

Subacute sclerosing panencephalitis (SSPE) usually arises in children who had measles in their infancy. The virus persists in the central nervous system and, years later, gives rise to a disease of insidious onset and chronically progressive course, leading to death in two to three years. The initial presentation is with mental abnormalities such as irritability, fatigability, and impaired cognitive performance. Involuntary movements and noise-induced myoclonus appear a few weeks later. Finally, the child develops generalized spasticity and

the prodromal phase (10.1.79), only a hint of periodic activity is seen. It is fully developed 1 month later (11.1.79) and slowly declines in amplitude in the ensuing months.

severe, progressive dementia. The EEG reveals periodic, high-amplitude slow waves. The illness is always fatal.

Other illnesses whose pathogenetic mechanisms are probably similar are progressive rubella panencephalitis and the various types of encephalitis arising a few days or weeks after an infectious illness (measles, mumps, chickenpox, rubella).

Postvaccinal encephalitis. It has been hypothesized, but never proved, that encephalitis can rarely arise as a complication of vaccination against measles, rubella, or smallpox.

Intracranial Abscesses

Brain abscesses are produced by focal infection of the brain parenchyma leading to tissue destruction and pus formation. They can be solitary or multiple. A special form is focal encephalitis, in which systemic sepsis or the embolization of infectious material into the central nervous system gives rise to multilocular, disseminated microabscesses.

Brain Abscess

Etiology. Brain abscesses are caused by one or more pathogens, mainly streptococci and staphylococci and, less commonly, Pseudomonas, Actinomyces, and fungi. Like the organisms that cause bacterial meningitis, these pathogens can reach the brain through local extension of infection (especially mastoiditis, sinusitis, and otitis), hematogenous dissemination from a distant infectious focus (usually pulmonary infections or endocarditis), or direct contamination (open brain injury). Immunocompromised patients are at increased risk.

Clinical manifestations. A large brain abscess exerts mass effect and typically causes fever, leukocytosis, and

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Infectious Diseases of the Brain and Meninges 119

rapidly progressive intracranial hypertension. Marked perifocal edema generally adds to the mass effect.

Alternatively, there may be a subdural empyema between the dura mater and the arachnoid, or an epidural abscess between the dura mater and the inner table of the skull. These processes usually arise as a complication of sinusitis or otitis, less commonly after trauma. Fever, headache, and meningism, accompanied by neurological deficits, are their clinical hallmarks. The course of subdural empyema is often fulminant and lifethreatening, that of epidural abscess usually more protracted.

Diagnostic evaluation. The diagnosis is suspected on the basis of the typical clinical findings (intracranial hypertension with papilledema, impaired consciousness, sometimes hemiparesis or other focal neurological deficits), accompanying signs of infection (fever, elevated laboratory parameters of inflammation), and relevant aspects of the past medical history (such as traumatic brain injuries, known lung or heart disease, and immune suppression or diseases of the immune system). CSF examination may reveal inflammatory changes (predominantly granulocytic pleocytosis, elevation of total protein), and the CT or MRI scan shows a ring-shaped area of contrast enhancement (abscess wall) surrounding the hypodense interior of the abscess.

Treatment. Operative removal of the abscess is the preferred form of treatment in most patients, accompanied by antibiotic therapy, which is initiated before surgery and continued thereafter for at least six weeks.

Focal Encephalitis

Etiology. Focal encephalitis consists of multilocular foci of infection in the brain parenchyma (Fig. 6.31), produced either by the seeding of the brain with bacteria in generalized sepsis (metastatic focal encephalitis) or by the embolization of multiple infectious microthrombi into the cerebral vasculature (embolic focal encephalitis). The latter is usually a complication of subacute bacterial endocarditis, which, in turn, is most often caused by Streptococcus viridans. In contrast, the septic form may be secondary to purulent infection in practically any area of the body. Streptococcal and staphylococcal infections are the usual causes.

Fig. 6.31 Embolic focal encephalitis and brain abscesses (T1weighted MRI after the administration of contrast medium).

Clinical manifestations. The typical findings include signs of a generalized septic illness (high fever, rigors) combined with focal brain signs, impaired consciousness, and, not uncommonly, psychosis. The neurological and psycho-organic signs fluctuate in severity. They manifest themselves in bouts, with remissions in between.

!A septic illness accompanied by fluctuating mental status on neurological abnormalities should raise suspicion of focal encephalitis.

Diagnostic evaluation. The diagnosis is suspected from the clinical findings and, possibly, inflammatory CSF changes, and confirmed by a CT and/or MRI scan demonstrating multiple small lesions in the brain. A heart murmur should always be listened for. Blood should be drawn for culture during the upward phase of the fever curve, and during rigors; blood culture may reveal the responsible pathogen.

Treatment. Antibiotic therapy is indicated and should be tailored to the sensitivity profile of the responsible organism, if it can be identified.

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Diseases of the Brain and Meninges

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120 6 Diseases of the Brain and Meninges

Metabolic Disorders and Systemic Illnesses Affecting

the Nervous System

The intense metabolic activity of the nervous system (both central and peripheral) makes it vulnerable to damage by a wide variety of metabolic disorders, both congenital (inborn errors of metabolism, i. e., metabolic diseases in the narrower sense of the term) and acquired (e. g., toxic). These disorders manifest themselves clinically as metabolic encephalopathy and metabolic neuropathy, of which there are many different types. Involvement of the nervous system by general medical illnesses (e. g., endocrinopathy or vasculitis) and paraneoplastic syndromes affecting the nervous system can present in similar ways.

Congenital Metabolic Disorders

Metabolic diseases are caused by hereditary enzyme defects. They usually present in early childhood but sometimes not until many years later. They can be roughly divided into disorders of lipid, amino acid, and carbohydrate metabolism. Wilson disease is due to a disturbance of copper metabolism.

General clinical manifestations. The following findings in children and adolescents suggest the presence of a metabolic disease:

delayed motor and cognitive development,

a slowly worsening course,

progressive spasticity,

progressive dementia,

optic nerve involvement,

epileptic seizures,

accompanying polyneuropathy and myopathy,

a positive family history of similar manifestations.

Diagnostic evaluation. In general, the diagnostic workup includes:

the taking of a comprehensive family and personal history,

a clinical neurological (neuropediatric) examination,

amino acid screening of the urine,

measurement of the serum concentration of glucose, ammonia, lactate, and pyruvate and screening for the lysosomal enzymes arylsulfatase A, hexosaminidase, and α-galactosidase,

lightand electron-microscopic examination of biopsied tissue samples, with routine and special stains,

radiologic examination of the skeleton,

MRI of the brain.

Disorders of Lipid Metabolism

Lipid storage diseases are caused by faulty enzymatic degradation of individual lipid substances, leading to deposition of the intermediate products of lipid metabolism in various internal organs (liver, spleen, bone marrow) and in the nervous system. Disorders in which these nondegradable metabolites accumulate mainly in the neurons of the brain are characterized by degeneration of the cerebral cortex or of the subcortical nuclear areas (lipidoses); disorders in which they accumulate mainly in white matter are characterized by demyelination of the cerebral white matter and/or peripheral nerve sheaths (leukodystrophies). The lipid storage diseases affecting the nervous system are listed in Table 6.17. Two examples of the radiologic appearance of the brain in the leukodystrophies are shown in Fig. 6.32.

Disorders of Amino Acid and Uric Acid

Metabolism

The more common disorders of these types include phenylketonuria (an autosomal recessive disorder of amino acid metabolism), maple syrup urine disease, Hartnup disease, and homocysteinuria (Table 6.18).

Disorders of Carbohydrate Metabolism

These disorders include the monosaccharidoses (e. g., galactosemia), the glycogenoses, and the mucopolysaccharidoses (Table 6.19). Myoclonus epilepsy, a type of mucopolysaccharidosis, is characterized by generalized epileptic seizures, myoclonus, and dementia.

Disorders of Copper Metabolism

A disturbance of copper metabolism causes hepatolenticular degeneration (Wilson disease), an autosomal recessive disorder whose genetic locus lies on the long arm of chromosome 13. The concentration of the copper transport protein ceruloplasmin is abnormally low and, as a result, the serum free copper concentration is high and an abnormally large amount of copper is eliminated in the urine. Free copper is deposited in the liver, the edge of the cornea (producing the typical Kayser− Fleischer ring), and the brain. Hepatopathy dominates the clinical picture in childhood and the neurological manifestations come later; the most impressive of these is a coarse postural and intention tremor of the extremities (recognizable on extension of the arms to both sides, for example, as a “flapping tremor”). Dysarthria, dystonia, and rigidity are common, as are mental abnormalities (depression, personality changes, or even psychotic episodes). The Kayser−Fleischer ring, a brown ring around the periphery of the cornea, helps to establish the diagnosis. MRI reveals cortical atrophy, enlarged ventricles, and signal abnormalities in the basal ganglia. This disorder is treated with D-penicillamine or zinc sulfate.

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Metabolic Disorders and Systemic Illnesses Affecting the Nervous System 121

Fig. 6.32 Leukodystrophies (T2weighted MRI images). a MRI in an 8- year-old boy: symmetrical, diffuse signal abnormalities in the white matter of the occipital and parietal lobes.

b MRI in a 43-year-old man: symmetrical signal abnormalities in white matter.

	a		b
Table 6.17 Lipidoses and leukodystrophies affecting the nervous system
Diseases	Clinical features	Remarks
Lipidoses
GM1-gangliosidoses and	infantile progressive encephalopathy, progressive	galactosidase deficiency in GM1-gangliosidoses; he-
GM2-gangliosidoses	myopathy in adults; possibly myoclonus, convul-	xosaminidase deficiency in GM2-gangliosidoses, in-
	sions, visual impairment, progressive spasticity and	cluding Tay−Sachs disease and Sandhoff disease,
	dementia; muscle atrophy and progressive weak-	with characteristic cherry-red spot
	ness
Fabry disease (angiokera-	onset of symptoms in childhood or adolescence;	X-linked inheritance; α-galactosidase deficiency
toma corporis diffusum)	burning pain in the limbs, particularly in warm sur-	with intracellular accumulation of trihexosylcera-
	roundings; deficient sweating; maculopapular, pur-	mides
	plish-red skin changes; renal failure; frequent cere-
	brovascular accidents
Gaucher disease	diverse neurological manifestations, gaze paresis,	autosomal recessive inheritance, glucocerebro-
juvenile and adult forms	bulbar signs, spasticity, polyneuropathy, psychosis,	sidase deficiency; foam cells in bone marrow
	dementia, myoclonus, epileptic seizures
Niemann−Pick disease	progressive developmental delay beginning in the	autosomal recessive inheritance; genetic defect in
	first year of life; juvenile forms with encephalopa-	Ashkenazi Jews
	thy or hepatomegaly, progressive dementia, spasti-
	city, and ataxia as well as epileptic seizures and
	psychosis

Refsum disease (heredo-	onset of symptoms in middle age; night blindness
pathia atactica polyneuri-	due to retinitis pigmentosa, hearing loss, polyneu-
tiformis)	ropathy with areflexia and gait ataxia; mental ab-
	normalities
Cerebrotendinous xant-	onset of symptoms in adolescence or later; mental
homatosis (cholestanol	retardation; juvenile cataracts, progressive spasti-
storage disease)	city and ataxia; xanthomas, particularly on exten-
	sor tendons and Achilles’ tendons; polyneuropathy
	and muscle atrophy

lack of phytanic acid α-dehydrogenase, accumulation of phytanic acid in the body (liver, kidneys, nervous system); a low-phytanic-acid diet and plasmapheresis are effective treatments

autosomal recessive inheritance; impaired synthesis of bile acids; accumulation of cholestanol in plasma and brain, tendon xanthomas

Neuronal ceroid	presentation in infancy and early childhood (Spiel-
lipofuscinosis	meyer−Vogt type) or in adulthood (Kufs disease);
(Batten−Kufs disease)	ataxia, myoclonus, epileptic seizures, progressive
	visual loss and mental deterioration
Leukodystrophies:
Metachromatic	late infantile type: from the age of 1 year onward,	autosomal recessive inheritance; lack of arylsulfa-
leukodystrophy	spastic weakness progressing toward quadriplegia,	tase A; accumulation of sulfatide in the brain, peri-
	loss of mental function, areflexia, bulbar and pseu-	pheral nerves, and other tissues; demonstration of
	dobulbar signs, optic atrophy;	arylsulfatase A deficiency in leukocytes and urine
	juvenile type: presentation at age 2−10 years, ele-
	vated CSF protein, white matter hypodense in CT
	and hyperintense in T2-MRI
Globoid cell leukodys-	infantile, juvenile, and adult types; spasticity, optic	lack of galactocerebrosidase
trophy (Krabbe disease)	atrophy, and polyneuropathy

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Diseases of the Brain and Meninges