122	6 Diseases of the Brain and Meninges
		Table 6.18 Disorders of amino acid and urate metabolism
		Disease	Clinial features	Remarks
		Phenylketonuria	clinical manifestations from the age of 6 months on-	autosomal recessive inheritance; lack of hydroxylation
			ward, if untreated: mental retardation, epileptic	of phenylalanine to tyrosine; treated with a low-
			seizures, spasticity, tremor, hypopigmentation	phenylalanine diet; neonatal screening (Guthrie test)
		Maple syrup urine	presentation in the neonatal period: impaired alert-	impaired degradation of branched amino acids;
		disease	ness, diminished muscle tone, mental retardation	sweet-smelling urine (like maple syrup)
		Hartnup disease	bouts of pellagralike dermatitis, accompanied by epi-	impaired tubular and intestinal resorption of tryp-
			sodes of ataxia, nystagmus, and gait unsteadiness,	tophan; aminoaciduria
			progressive dementia, and spasticity
		Homocysteinuria	arterial and venous thromboembolism, lens ectopy,	impairment of methionine metabolism
			mental retardation
		Table 6.19 Disorders of carbohydrate metabolism
		Disease	Clinical features	Remarks
		Galactosemia	onset in infancy: failure to thrive, retardation, jaun-	impaired enzymatic degradation of galactose; accu-
			dice, cataracts	mulation of the phosphorylated form in the liver, kid-
				neys, lenses, and brain

Glycogenoses,	accumulation of glycogen in the liver, kidneys, mus-
types I−XI	cles, and brain; clinically, hepatic dysfunction, possibly
	myopathy, mental retardation, epileptic seizures
Mucopolysacchari-	Pfaundler−Hurler syndrome:
doses	onset in infancy, corneal opacification, joint swelling,
	dwarfism, mental retardation, possibly quadriparesis
	due to spinal cord compression
	Scheie syndrome:
	juvenile type, with slow progression
	Progressive myoclonus epilepsy (Lafora type):
	generalized epileptic seizures, myoclonus, progressive
	dementia, psychosis

impaired enzymatic degradation of glycogen

deposition of acidic mucopolysaccharides in various tissues, due to hydrolase deficiency deposition of mucopolysaccharides in the form of Lafora bodies in the brain, muscles, and liver

Other Metabolic Disorders

A number of other metabolic disorders must be mentioned here for completeness, some of which are of as yet unknown causes. Adrenoleukodystrophy is due to an inherited defect of the X chromosome, which causes a deficiency of lignoceroyl coenzyme A synthetase. Most patients are male. In the first or second decade of life, they develop spastic gait disturbances, visual impairment, and mental changes. Affected adults may develop adrenal insufficiency. In adrenomyeloneuropathy, the same manifestations are present, with polyneuropathy in addition. Reye syndrome is probably of multifactorial origin. A few days after a viral illness, the patient becomes progressively somnolent, with nausea, delirium, and cerebral edema. In the various types of α-lipo- proteinemia, the serum cholesterol and triglyceride levels are abnormally low. These disorders are clinically characterized by ataxia, nystagmus, disturbances of eye movement, and polyneuropathy, in combination with retinitis pigmentosa. These manifestations are often accompanied by acanthocytosis (Bassen−Kornzweig).

Acquired Metabolic Disorders

Intoxications

Medications, recreationally used substances, drugs of abuse, industrial toxins, and numerous other substances can exert a toxic influence on the nervous system.

Intoxications of the nervous system are classified according to their clinical presentation in Table 6.20, which also includes iatrogenic intoxications.

Alcohol-induced Disorders of the Nervous System

Because of their importance in clinical practice, the effects of alcohol on the nervous system are listed in detail in a separate table (Table 6.21).

Mumenthaler / Mattle, Fundamentals of Neurology © 2006 Thieme All rights reserved. Usage subject to terms and conditions of license.

Metabolic Disorders and Systemic Illnesses Affecting the Nervous System 123

Table 6.20 Neurological manifestations of toxic or iatrogenic origin

Neurological signs and	Causes
syndromes
Headache	nearly all headache preparations when overused; withdrawal of caffeine, ergotamine, or am-
	phetamine; oral contraceptives and other hormone preparations (pseudotumor cerebri); nitrates,
	aminophylline, tetracycline, sympathomimetics, IV immunoglobulins, tamoxifen, H2-antagonists
Ischemic stroke	oral contraceptives and other hormone preparations, antihypertensive agents, ergotamine, am-
	phetamine, cocaine, sympathomimetics, intra-arterial methotrexate, angiography, interventional
	intra-arterial procedures, cardiovascular surgery, radiotherapy, fat injection (“liposculpturing”),
	chiropractic manipulation
Hemorrhage (intracerebral,	anticoagulants, fibrinolytic agents, inhibitors of platelet aggregation, amphetamine, cocaine, sym-
extracerebral, spinal)	pathomimetics; femoral nerve palsy due to psoas hematoma
Epileptic seizures	antibiotics (penicillin, isoniazid), general and local anaesthetics (e. g., lidocaine), insulin, radiologi-
	cal contrast media, withdrawal of benzodiazepines or other sedatives, anticonvulsant withdrawal,
	phenytoin overdose, antidepressants, aminophylline and theophylline, phenothiazines, penta-
	zocine, tripelennamine, cocaine, meperidine, cyclosporine, antineoplastic agents, other

Coma

Neurasthenic symptoms, acute and chronic encephalopathy

Extrapyramidal movement disorders (acute dystonia, dyskinesia, akathisia, drug-induced parkinsonism, tardive dyskinesia)

Cerebellar ataxia

insulin, barbiturates, benzodiazepines and other sedatives, analgesics, other

heavy metals, lithium, aluminum, heroin pyrolysate, cyclosporine, anticholinergics, dopamine agonists, benzodiazepines and other sedatives, antihistamines, antibiotics, anticonvulsants, corticosteroids, H2-antagonists, disulfiram, methotrexate, organic solvents, hallucinogens, radiotherapy, dehydration, water intoxication, dialysis encephalopathy, other

neuroleptics (phenothiazines, thioxanthenes, butyrophenones, dibenzapines), antiemetics containing metoclopramide or phenothiazines, dopamine agonists, levodopa, antihypertensive agents

(e. g., reserpine, captopril), flunarizine, cinnarizine, MPTP

phenytoin, carbamazepine, barbiturates, lithium, organic solvents, heavy metals, acrylamide, 5- fluorouracil, cytosine arabinoside, procarbazine, hexamethylmelamine, vincristine, cyclosporine, ciguatera fish poisoning

Central pontine myelinolysis	too rapid correction of hyponatremia
Malignant neuroleptic syn-	neuroleptics
drome
Malignant hyperthermia	succinylcholine, halothane, other general anaesthetics
Polyneuropathy	see p. 176 ff.
Optic neuropathy	tobacco, ethanol, methanol, myambutol
Deafness	aminoglycosides, cytostatic agents
Disorders of neuromuscular	penicillamine, muscle relaxants, procainamide, magnesium, quinine, aminoglycosides, α-interferon
transmission
Myopathy and rhabdomyolysis	ethanol, cocaine, heroin and other opiates, pentazocine, benzene, corticosteroids, thyroxine, anti-
	malarial agents, colchicine, antilipid agents (fibrates and statins), zidovudine, cyclosporine, diuret-
	ics (via hypokalemia), ipecac

Table 6.21 Effects of alcohol on the nervous system

Clinical condition	Features	Remarks
Acute alcohol	euphoria, dysphoria, disinhibition, ataxia, som-	respiratory arrest may cause death
intoxication	nolence, stupor
Alcohol withdrawal	diaphoresis, tachycardia, insomnia, tremor, hallucina-	when the patient’s alcohol intake is cut off, the blood
syndrome, delirium	tions, epileptic seizures, psychomotor agitation,	alcohol level falls and the patient passes through the
tremens	possibly delirium	stages of alcohol withdrawal syndrome, from mild au-
		tonomic symptoms to predelirium and delirium; full
		delirium (delirium tremens) is the most severe form
		of the alcohol withdrawal syndrome; treated with
		clomethiazole
Alcoholic dementia	chronic alcohol abuse with systemic effects on the	brain atrophy, visible in CT and MRI, reversible with
	liver and peripheral nervous system	abstinence
Wernicke	memory impairment, confusion, oculomotor dysfunc-	signal abnormalities around the cerebral aqueduct
encephalopathy	tion (abducens palsy, nystagmus, conjugate gaze	and third ventricle in T2-weighted MRI; caused by thi-
	palsy), ataxia, dysarthria	amine deficiency and malnutrition; often combined
		with Korsakoff psychosis
		Continued

blubber blubber

Mumenthaler / Mattle, Fundamentals of Neurology © 2006 Thieme All rights reserved. Usage subject to terms and conditions of license.

6

Diseases of the Brain and Meninges

124	6 Diseases of the Brain and Meninges
		Table 6.21 Effects of alcohol on the nervous system (Continued)
		Clinical condition	Features	Remarks
		Korsakoff	acute amnestic syndrome with anterograde and ret-	thiamine deficiency; seen also in nonalcoholics
		syndrome	rograde amnesia, confabulation, reduced drive, and
			reckless behavior
		Marchiafava−	acute confusion, epileptic seizures, impairment of	predominantly seen in Italian drinkers of red wine
		Bignami syndrome	consciousness; demyelination of corpus callosum and
			centrum semiovale; patients who survive the acute
			phase are often abulic and demented

Alcoholic cerebellar	progressive limb ataxia mainly affecting the lower
degeneration	limbs, with impairment of gait
Central pontine	confusion, followed within a few days by dysphagia,
myelinolysis	dysarthria, quadriparesis with pyramidal tract signs,
	and oculomotor disturbances (bilateral abducens
	palsy or horizontal conjugate gaze palsy); progressive
	impairment of consciousness, later development of
	the locked-in syndrome
Alcoholic	predominantly sensory polyneuropathy, often painful;
polyneuropathy	distal sensory deficit in the lower limbs, loss of re-
	flexes
Fetal alcohol	caused by maternal alcoholism; short stature, psycho-
syndrome (alcohol	motor retardation, microcephaly, facial dysmorphism
embryopathy)	(stub nose, thin lips, micrognathism)

seen in malnourished chronic alcoholics, also as an iatrogenic process after excessively rapid correction of hyponatremia; also in liver disease

Endocrine Diseases

Neurological manifestations often accompany dysfunction of the endocrine glands, particularly the thyroid gland, the parathyroid glands, the pancreatic islet cells, and the adrenal gland.

Hypothyroidism causes cretinism in infants, mental retardation and short stature in children. In adults, it can cause ataxia, dysarthria, and nystagmus, a predominantly sensory polyneuropathy, and muscle weakness, with characteristically delayed relaxation of muscle fibers after elicitation of the deep tendon reflexes. Mental abnormalities may also be present (apathy, depression, dementia, delirium).

Table 6.22 Clinical manifestations of hypoglycemia

Autonomic manifestations

Dizziness, diaphoresis, nausea, pallor, palpitations, precordial pressure, abdominal pain, hunger, anxiety, headache

Cerebral manifestations

paresthesiae, blurred vision, diplopia, tremor, unusual or abnormal behavior

epileptic seizures: simple partial, complex partial, or generalized

impairment of consciousness ranging from somnolence to coma

focal neurological deficits, e. g., hemiparesis, hemianopsia, aphasia, apraxia

Permanent neurological deficits (after prolonged or repeated episodes of hypoglycemia)

cognitive deficits, dementia

cognitive deficits of focal type, focal neurological deficits

mainly distal muscular atrophy due to damage of anterior horn cells and axons

Hyperthyroidism can produce, in addition to its characteristic general manifestations (nervousness, insomnia, tremor, sweating, tachycardia, diarrhea, heat intolerance), a variety of neurological deficits:

cerebral manifestations: irritability, psychotic episodes, tremor, choreoathetosis, spastic elevation of muscle tone, pyramidal tract signs;

ocular manifestations: diminished frequency of blinking (Stellwag sign), ophthalmoplegia, diplopia, optic neuropathy; in Graves disease, lid retraction (Graefe sign), weakness of convergence (Möbius sign), exophthalmos;

muscular manifestations: thyrotoxic myopathy with mainly proximal weakness, myasthenia gravis, and thyrotoxic periodic paralysis;

partial and generalized epileptic seizures;

rarely, polyneuropathy.

Hypoparathyroidism. A deficiency of parathyroid hormone causes hypocalcemia, leading to tetany, epileptic seizures, intracranial hypertension with headache and papilledema, hypomotor and hypermotor movement disorders, and neurastheniform mental manifestations and delirium.

Hyperparathyroidism. An excess of parathyroid hormone manifests itself clinically mainly through behavioral disturbances (emotional lability, agitation, fatigability, and confusional states) and dementia-like cognitive impairment, in addition to muscle weakness, ataxia, dysarthria, and sometimes spasticity and epileptic seizures.

Disturbances of insulin metabolism. Hyperinsulinism is one of the possible causes of hypoglycemia, which causes the neurological manifestations listed in Table 6.22. The most prominent neurological manifestation of

Mumenthaler / Mattle, Fundamentals of Neurology © 2006 Thieme All rights reserved. Usage subject to terms and conditions of license.

Metabolic Disorders and Systemic Illnesses Affecting the Nervous System 125

the insulin deficiency of diabetes mellitus is polyneuropathy (see p. 176); in addition, diabetic arteriopathy may secondarily harm the nervous system (ischemic stroke, mononeuropathies of peripheral or cranial nerves).

Gastrointestinal Diseases

Leukemia often leads to cerebrovascular complications (hemorrhage, infarct, venous sinus thrombosis). Onethird of leukemia patients have a meningeal leukemic infiltrate (leukemic meningitis). Leukemic infiltrates can cause various kinds of focal deficits of the central and peripheral nervous system.

Collagen Diseases and Immune Diseases

Gastrointestinal diseases can cause toxic damage to the nervous system (e. g., in hepatic dysfunction). The nervous system can also be harmed by secondary nutritional deficiencies and hypovitaminoses (e. g., in stomach diseases and intestinal resorptive disorders).

Neurological manifestations are commonly seen in hepatic diseases, particularly chronic hepatopathy with portal hypertension, and a portacaval shunt. Ammonia and other toxic substances bypass the portal circulation, enter the systemic circulation, and are transported to the brain, where they cause hepatic encephalopathy. This disorder is characterized at first by somnolence and apathy, later by progressive impairment of consciousness and delirium. As in renal insufficiency, asterixis can be seen (see below). In addition, there may be spasticity, with exaggerated deep tendon reflexes and pyramidal tract signs.

Other gastrointestinal diseases. In sprue, impaired intestinal resorption can cause malnutrition, which in turn causes polyneuropathy and cerebellar ataxia (vitamin B12 deficiency). The gliadin antibodies that are present in sprue are also often associated with ataxia. Crohn disease may be accompanied by myelopathy and muscle weakness, while ulcerative colitis may be accompanied by peripheral neuropathy.

Hematologic Diseases

Hematologic diseases can alter the viscosity and coagulability of the blood, putting the patient at risk of thrombosis or hemorrhage. They can also alter its transport properties (quantitative and structural anomalies of the blood cells or plasma proteins). Finally, some hematologic diseases involve malignant neoplasia of certain types of blood cells. All of these phenomena can have damaging effects on the nervous system.

Anemia reduces the oxygen-carrying capacity of the blood and can lead to cerebral hypoxic (ischemic) manifestations. The vitamin B12 deficiency of untreated pernicious anemia causes funicular myelosis (p. 153) and polyneuropathy (cf. Table 10.1, p. 176).

Polycythemia vera is associated with headache, dizziness, and paresthesiae, as well as ischemic stroke and extrapyramidal manifestations.

Collagenoses affect not only the skin, joints, and internal organs, but also the nervous system. Secondary damage of nervous tissue (ischemia and/or hemorrhage) occurs because of inflammatory changes of the blood vessels of the brain, spinal cord, and peripheral nerves (vasa nervorum). These vascular changes are mostly produced by autoimmune mechanisms.

In this section, we will merely list the neurological manifestations of the main types of collagen disease. More detailed discussions can be found in textbooks of internal medicine.

!Though collagen diseases and vasculitic conditions are only briefly discussed in this book, the clinician must keep them in mind when formulating the differential diagnosis of practically any condition with neurological manifestations.

Collagen diseases are diagnosed by their typical clinical manifestations, the demonstration of specific (auto-)an- tibodies in the serum, and further evidence derived from angiography or from biopsies of tissue and/or blood vessels.

Periarteritis nodosa. In the nervous system, this disease causes polyneuropathy and mononeuropathies and, less commonly, focal deficits of the central nervous system or epileptic seizures.

Churg−Strauss syndrome. The main clinical manifestations of this disorder, closely related to periarteritis nodosa, are bronchial asthma and eosinophilia; polyneuritis is the main neurological manifestation.

GANS (granulomatous angiitis of the central nervous system) is a vasculitic disorder, restricted to the cerebral vessels, that causes multiple thrombotic strokes.

Temporal arteritis. Intractable headache is the main symptom of this disease. The temporal artery is thickened (at least on one side) and, in advanced disease, no longer pulsates. A more extensive discussion of this disease can be found on page 250.

Wegener granulomatosis is a systemic, necrotizing vasculitis that primarily involves the kidneys and the upper airways, but can also cause mononeuritis (of the cranial nerves as well) and focal manifestations in the central nervous system.

blubber blubber

Mumenthaler / Mattle, Fundamentals of Neurology © 2006 Thieme All rights reserved. Usage subject to terms and conditions of license.

6

Diseases of the Brain and Meninges

126 6 Diseases of the Brain and Meninges

	Systemic lupus erythematosus only rarely presents		such cases can be considered a type of metabolic en-
	with neurological deficits, but more than half of all		cephalopathy. Hyponatremia and hypo-osmolality cause
	patients develop neurological and/or psychiatric		cerebral edema, which presents clinically with head-
	manifestations as the disease progresses. The most		ache, nausea, impaired attention and concentration,
	common types are headache, neuropsychological defi-		epileptic seizures, and a progressive decline of con-
	cits and behavioral abnormalities, focal neurological		sciousness. Hypernatremia and hyperosmolality lower
	deficits, and spinal cord transection syndromes, fol-		the water content of the brain and, therefore, also its
	lowed by neuritis and myopathy.		volume, and cause cognitive impairment and a progres-
	Sarcoidosis (Boeck disease) is characterized by the for-		sive decline of consciousness. The generalized hyper-
			coagulable state characterizing these conditions may
	mation of multiple granulomas in the lungs and other		lead to venous sinus thrombosis. Alternatively, as the
	internal organs. Depending on their location,		brain shrinks from loss of water, bridging veins may be
	granulomas in the nervous system can cause chronic		torn, producing a subdural hematoma.
	meningitis (p. 113), encephalitic manifestations (dia-		A rapid return of sodium concentration from below
	betes insipidus, hemiparesis, ataxia), cranial nerve pal-		normal (hyponatremic) toward normal values is
	sies, or mononeuritis multiplex (p. 179).		thought to be the cause of central pontine myelinolysis,
			i. e., bilaterally symmetrical demyelination of the white
	Renal Failure and Electrolyte Disturbances		matter of the base of the pons. Clinically, the disorder
			presents with impairment of consciousness, dysphagia,
			dysarthria, and spastic quadriparesis, and sometimes
	Electrolyte disturbances can impair the function-
			oculomotor dysfunction (horizontal gaze paresis).
	ing of the brain (impairment of consciousness and/		Severe cases can cause the “locked-in syndrome” (p. 77)
	or cognition, generalized epileptic seizures) and of		or decerebrate rigidity.
	the neuromuscular junction (overexcitability, e. g.,		Disturbances of potassium, calcium, and magnesium
	in tetany due to hypocalcemia; underexcitability,		balance, as well as hypophosphatemia, can affect
	e. g., in disorders of potassium metabolism with		muscular function, sometimes dramatically. Hypoka-
	episodic paralysis, see p. 271). Electrolyte distur-		lemia or hyperkalemia can cause flaccid paralysis of pe-
	bances, particularly those affecting sodium con-		ripheral neurogenic type, as well as disturbances of my-
	centration, are often caused by renal failure. In		ocardial excitability. Hypocalcemia or hypomagnesemia
	renal disease, the pathological retention of sub-		causes tetany; hypercalcemia or hypermagnesemia
	stances normally excreted in the urine has further		causes metabolic encephalopathy with slowing, confu-
	toxic effects.		sion, and impairment of consciousness. Hypo-
			phosphatemia causes peripheral weakness.
	Acute renal failure causes uremic encephalopathy,		Malignancy
	which is characterized by progressive impairment of
	concentration and short-term memory, followed by im-		Malignant neoplasia can impair the functioning of
	pairment of consciousness and delirium. These abnor-
			the nervous system by direct tumor	invasion,
	malities of mental state are often accompanied by dys-
			metastasis (p. 95), or long-distance	humorally
	arthria, gait unsteadiness, and ataxia. Myoclonus and as-
			mediated effects (paraneoplastic syndromes).
	terixis (bilateral, irregular back-and-forth movements of
	the fingers when the arms are extended; sometimes,		Paraneoplastic effects can, in principle, occur in any
	analogous motor phenomena in other parts of the body
	as well) are seen in nearly all patients.		type of malignancy, but are especially common in small-
	Chronic renal failure may lead to the development of		cell bronchial carcinoma. Paraneoplastic syndromes
			often become clinically evident while the primary
	polyneuropathy and “restless legs syndrome” (p. 261).		tumor is still asymptomatic. They can predominantly af-
	Patients undergoing dialysis may develop the dialysis		fect the central nervous system, the spinal nerve roots,
	disequilibrium syndrome (nausea, agitation, delirium,		the peripheral nerves, or the muscles. They are diag-
	convulsions). Those who have been treated with dialysis		nosed based on their clinical findings, combined with
	for a long time are at risk for dialysis encephalopathy		the identification of the responsible tumor; the diagno-
	(dialysis dementia), with dysarthria, ataxia, and convul-		sis can be confirmed, in many patients, by the demon-
	sions.		stration of more or less specific antineuronal antibodies.
	Electrolyte disturbances. Disturbances of sodium con-		Nonetheless, paraneoplastic syndromes are still, in
			general, diagnoses of exclusion. Some of the paraneo-
	centration alter the serum osmolality and are the type		plastic syndromes affecting the nervous system are
	of electrolyte disturbance most commonly causing neu-		listed in Table 6.23, together with the primary tumors
	rological dysfunction. The neurological condition in		that cause them.

Mumenthaler / Mattle, Fundamentals of Neurology © 2006 Thieme All rights reserved. Usage subject to terms and conditions of license.