Thieme Mumenthaler, Neurology - part 4 doc

Table 2.70 MRI findings of metabolic orders and some neurodegenerative dis-orders 729 Disorders mainly affecting the white matter of the brain leukodystro-phies: > Disorders of amino ac

Table 2.70 MRI findings of metabolic

orders and some neurodegenerative

dis-orders (729)

Disorders mainly affecting the white

matter of the brain

(leukodystro-phies):

> Disorders of amino acid metabolism

> Lysosomal disorders and other

– Degenerative diffuse sclerosis of

neutral lipid type

– Pelizaeus-Merzbacher disease

– Batten-Kufs disease

– Adrenoleukodystrophy

– Diffuse cerebral sclerosis (Schilder’s

disease, encephalitis periaxialis

dif-fusa)

> Spongiform degeneration of the

ner-vous system (Canavan’s disease)

Disorders mainly affecting the gray

matter of the brain:

> Tay-Sachs disease and other lipidoses

> Hurler syndrome and other

muco-polysaccharidoses (325)

> Mucolipidoses and fuscinoses

> Glycogen storage diseases

Disorders affecting both white and

> Pantothene kinase-associated

neuro-degeneration (formerly

Hallervorden-Spatz disease) (30, 829)

> Huntington’s disease

Table 2.71 Lysosomal and other storage

diseases affecting the nervous system

Lipidoses:

GM2gangliosidosesGM1gangliosidosesFabry’s disease (angiokeratoma corporisdiffusum)

Gaucher’s diseaseNiemann-Pick diseaseFarber’s lipogranulomatosisWolman’s diseaseRefsum’s diseaseCerebrotendinous xanthomatosisNeuronal ceroid lipofuscinosis

Leukodystrophies:

Metachromatic leukodystrophyKrabbe’s globoid cell leukodystrophy

Mucopolysaccharidoses Mucolipidoses

oclonus and generalized seizures inthe first few months of life, followed

by blindness, decorticate posturing,and death at 3–5 years The diagnosis

is made either by enzyme assay or bydirect DNA analysis (the preferredmethod) In both Tay-Sachs disease

and Sandhoff disease, a clinically

simi-lar disorder affecting non-Jewish fants, a characteristic cherry-red spot

in-is seen on the macula of the retina.Adult forms of hexosaminidase defi-ciency lead to dementia, spasticity,ataxia, and muscular atrophy, or else

to motor neuron disease, as seen inthe Kugelberg-Welander and Aran-Duchenne syndromes MRI reveals T2hyperintensity of the basal gangliaand cerebellar cortical atrophy (913,1042)

The G M1 gangliosidoses These

disor-ders are due to a deficiency of tosidase They clinically resemble

galac-Tay-Sachs disease (1041) and, like it,

may be diagnosed by enzyme assay

or by direct DNA analysis

Fabry disease (angiokeratoma

corpo-ris diffusum) (500) This X-linked

dis-order affects the skin, kidneys, and

blood vessels as well as the

periph-eral and autonomic nervous system

A deficiency of alpha-galactosidase

causes intracellular deposition of

tri-hexosylceramide The symptoms and

signs arise either because of the

pri-mary cellular involvement or because

of vascular compromise The initial

manifestations usually appear in

childhood or adolescence and consist

of burning pains in the extremities,

which are particularly severe in warm

weather, but respond to

diphenylhy-dantoin Sweating is lost soon

after-ward Maculopapular, reddish-purple

skin lesions appear, and, in the third

or fourth decade of life, kidney failure

occurs Stroke and acute vestibular

dysfunction are also common A mild

form of the disease may occur in

fe-male carriers of the gene

Gaucher’s disease This autosomal

re-cessive disorder is due to

glucocereb-rosidase deficiency, which results in

accumulation of glucocerebroside It

occurs in juvenile and adult neuronal

forms, as well as an adult

nonneuro-nal form In the juvenile form,

devel-opmental delay is evident in the first

few months of life, and affected

chil-dren die before their second birthday

The adult neuronal form causes

psy-chosis, dementia, myoclonus,

gener-alized seizures, akathisia,

supranu-clear gaze palsy, bulbar signs,

spastic-ity, and polyneuropathy, while the

nonneuronal form causes

splenomeg-aly, thrombocytopenia, bone erosion,

and bone pain Characteristic foam

cells (“Gaucher cells”) are found inthe bone marrow, and the enzymedeficiency can be detected in the leu-kocytes Enzyme replacement (intra-venous infusion of recombinant orhuman placental glucocerebrosidase)

is an effective, though expensive form

of treatment (67)

Niemann-Pick disease A deficiency of

acid sphingomyelinase (ASM)

under-lies both Type A and Type BNiemann-Pick disease These two dis-orders represent opposite ends of aspectrum of disease, in which pa-tients with lower levels of ASM activ-ity become ill earlier, have more se-vere neurologic involvement, and die

at an earlier age The inheritance tern is autosomal recessive, and theresponsible genetic defect lies onchromosome 18 (169) In Type A dis-ease, progressive encephalopathy ismanifest as dementia, spasticity,ataxia, and generalized seizures, andresults in death by the age of 2 years.Accompanying findings include acherry-red spot on the retinal macula(in some cases) and hepatospleno-megaly In Type B disease, organo-megaly and respiratory disturbancesare the most prominent clinical fea-tures, and patients may survive intoadolescence or adulthood

pat-Adult-onset Niemann-Pick disease(Types C, D, and E according to thecurrent nomenclature) is a differentdisease, due to a defect of cholesterolmetabolism; ASM activity may besecondarily impaired Hepatospleno-megaly is a prominent feature, andfoam cells are found in the bone mar-row and liver, as in Gaucher’s disease

A schizophrenia-like psychosis may

be the presenting sign (250).Type A or B disease may be diagnosed

by measurement of ASM activity in

leukocytes, or by DNA analysis Type

C disease is generally diagnosed by

specialized biochemical testing of

fi-broblasts obtained by skin biopsy

Refsum’s disease (heredopathia

atac-tica polyneuritiformis) (783)

Ref-sum’s disease is unusual in that it

in-volves storage of a substance derived

from the diet A deficiency of phytanic

acid alpha-dehydrogenase leads to

ac-cumulation of phytanic acid in the

tissues of the body, particularly the

liver and kidneys The first signs of

ill-ness may appear in childhood or as

late as middle age The most

promi-nent neurologic abnormalities are

night blindness secondary to retinitis

pigmentosa, sensorineural deafness,

polyneuropathy, and ataxia (both

ax-ial and appendicular) Psychiatric

manifestations may also be seen The

serum phytanic acid level is elevated,

and the enzyme defect may be

dem-onstrated in fibroblasts The patients’

condition improves on provision of a

low-phytanic-acid diet, and

plasm-apheresis can also be helpful (445,

907)

Cerebrotendinous xanthomatosis

(cholestanol storage disease) (76).

This autosomal recessive disorder is

due to an anomaly of bile acid

syn-thesis which results in the

accumula-tion of cholestanol in the plasma and

brain, as well as the formation of

xan-thomata of tendon sheaths (typically

on the Achilles tendon) and lungs

Al-though the xanthomata contain

cho-lesterol, the serum cholesterol level is

usually not elevated Mental

retarda-tion may begin early, but the

charac-teristic clinical picture, with

xantho-mata, cataracts, progressive

spastic-ity, and ataxia, does not develop until

adolescence or later Polyneuropathy

and muscle atrophy may also be seen.Dementia may develop in adulthood,and severe pseudobulbar signs mayappear in the preterminal phase;death usually ensues at some timebetween the ages of 30 and 60 Mo-lecular genetic diagnosis is possibleeven in the presymptomatic phase,and treatment with bile acids (cheno-deoxycholic acid) can mitigate thedisease manifestations and delaytheir progression (93, 658)

Other lipidoses Farber’s

lipogranulo-matosis and Wolman’s disease both

cause death a few months after birth

Patients with neuronal ceroid cinosis (Batten-Kufs disease) often die

lipofus-in lipofus-infancy or early childhood forms known, respectively, as Haltia-Santavuori disease and Jansky-Bielschowsky disease), but some sur-vive into adolescence (Spielmeyer-Vogt disease) or even adulthood (Kufsdisease) (94, 168) Ataxia, myoclonus,and intractable epilepsy are charac-teristic Adolescents suffer progres-sive loss of vision Patients with theadult form of the disease do not be-come blind, but do suffer from pro-gressive dementia (243)

fest in late infancy Spasticity appears

first, typically in the second year oflife, followed by deterioration ofmental function, disappearance of the

intrinsic muscle reflexes, and

devel-opment of bulbar and pseudobulbar

signs, including dysarthria Optic

at-rophy and blindness ensue, and,

fi-nally, quadriplegia and a persistent

vegetative state The juvenile form

ap-pears between the 3rd and 10th years

of life and is usually associated with a

gait disorder, sometimes also with

emotional disturbances and

demen-tia (864) The adult form becomes

manifest around age 30 with

psychi-atric abnormalities or dementia,

spasticity, and ataxia T2-weighted

MR images reveal confluent

hyperin-tensity of the cerebral and cerebellar

white matter The cortex is atrophic

(566) and the ventricles are dilated

The subcortical U-fibers are spared at

first, but are later involved as the

dis-ease progresses Biochemical analysis

of leukocytes and of urine reveals the

deficiency of arylsulfatase A The

pro-gression of the disease may be

slowed or halted by bone marrow

transplantation (543, 864)

Krabbe’s globoid cell leukodystrophy

(488) Galactocerebrosidase is the

missing enzyme in this disease,

whose most prominent signs are

spasticity, optic atrophy, and

dimin-ished nerve conduction velocity

When the disease arises in infancy, it

is fatal in the first 2 years of life

Child-hood and adult forms have also been

described, with clinical features

re-sembling those of metachromatic

leukodystrophy (976)

| Mucopolysaccharidoses (859)

The abnormalities of facial

appear-ance that are specific to this group of

diseases have been termed

“gargoyl-ism” (see under Hurler’s disease,

be-low) Each of these conditions is due

to a deficiency of a specific enzyme

(hydrolase), resulting in tion of acid mucopolysaccharides inthe tissues

accumula-Hurler’s disease This classic and

most severe type of ridosis begins in infancy and usuallyleads to death by age 10 A lumbargibbus deformity and corneal opacityare already evident in the first year oflife The joints become stiff and swol-len, the chest deformed; the handsand feet remain small and chubby,and stunted growth and mental retar-dation are evident by age 2 or 3 years.The facial features are coarse, typified

mucopolysaccha-by a projecting forehead, bushy brows, saddle nose, hypertelorism,and a lumpy tongue The meningesmay be thickened, and there may behydrocephalus or spinal cord com-pression leading to quadriparesis.Cardiac involvement is not infre-

eye-quently the cause of death Scheie’s disease is a variant of Hurler’s disease

with onset in childhood

Other mucopolysaccharidoses These

include Hunter’s, Sanfilippo’s, quio’s, and Maroteaux-Lamy diseases.

Mor-Hunter’s disease is X-linked recessive.Sanfilippo’s disease mainly affects thebrain, while the two last-named dis-eases mainly affect the skeleton

| Mucolipidoses (859)

These diseases, clinically similar tothe mucopolysaccharidoses, are diag-nosed by the finding of elevated oli-gosaccharide and glycopeptide levels

in the urine The sialidoses are a class

sub-Disorders of Amino Acid and Uric

Acid Metabolism

Phenylketonuria Phenylalanine

hy-droxylase deficiency, though rare, is

the most common disorder of amino

acid and protein metabolism It is

transmitted in an autosomal

reces-sive inheritance pattern In untreated

children, failure of hydroxylation of

phenylalanine to tyrosine impairs

ce-rebral myelination and causes mental

retardation and epilepsy Spasticity

and (often) tremor appear as the

dis-ease progresses The affected children

are often blond and blue-eyed,

be-cause tyrosine is a precursor of

mela-nin The clinical neurologic findings

are nonspecific T2-weighted MRI

re-veals hyperintensity of the white

matter (747) Since the 1960s, all

newborns have undergone diagnostic

screening for this disorder by

mea-surement of the serum phenylalanine

concentration A

phenylalanine-restricted diet enables

phenylketo-nurics to undergo normal motor and

mental development (682)

Maple syrup urine disease This

disor-der is an autosomal recessive enzyme

deficiency leading to impaired

me-tabolism of the branched-chain

amino acids valine, leucine, and

iso-leucine Like phenylketonuria, it is

as-sociated with mental retardation The

urine has a characteristic sweet smell

like that of maple syrup The

neurora-diologic findings are nonspecific

(T2-hyperintensity of white matter)

(138)

Hartnup disease (286) This

auto-somal recessive disorder is due to a

defect in the intestinal and renal

tu-bular transport of the neutral amino

acids tryptophan, alanine, and

histi-dine Characteristic findings include a

progressive, photosensitive, like dermatitis, ataxia, nystagmus,impaired gait, spasticity, and demen-tia (Hartnup was the surname of thefamily in which the disease was origi-nally described.)

pellagra-Homocystinuria This disorder of

me-thionine metabolism leads to arterialand venous thromboembolism, ecto-pia lentis, and mental retardation.Heterozygous carriers are at in-creased risk for stroke and occlusiveperipheral vascular disease

Reye’s syndrome This disease is

char-acterized by encephalopathy andfatty infiltration of the viscera It isdiscussed further below (p 296)

Disorders of Carbohydrate Metabolism

Glycogen storage diseases (235) ble 2.72 provides an overview of in-

Ta-herited enzyme deficiencies that pair the metabolism of glucose andglycogen Most are inherited in an au-tosomal recessive pattern; only type

im-IX and the hepatic form of type VIIIare X-linked recessive Glucose-6-phosphatase deficiency and glycogensynthetase deficiency are character-ized by recurrent hypoglycemic cri-ses, presenting with somnolence, stu-por, or coma and generalized sei-zures, which may cause lasting neu-rologic damage (p 898) The general-ized forms (types II, III, IV, and IX)cause intraneuronal glycogen storage,and thus mental retardation Skeletalmuscle involvement leads to exerciseintolerance, or to a myopathy resem-bling that of muscular dystrophy (p.895) In type IX glycogen storage dis-ease, severe hemolytic anemia may

be the major clinical finding

Type Eponym Deficient enzyme Involved organs and

I von Gierke Glucose-6-phosphatase Liver, kidney Hypoglycemic crises,

hepatomeg-aly

hypoto-nia, death by 1 year Infantile formAcid maltase Generalized Muscular dystrophy, respiratory

Acid maltase Generalized Proximal myopathy, respiratory

progressive weakness

hepatic failure

myalgia, contractures, nuria

erythrocytes

Mild hypoglycemia, aly

phosphofructo-kinase Skeletal muscle,erythrocytes Exercise-induced weakness,myalgia, contractures,

VIII Phosphorylase kinase Liver Asymptomatic hepatomegaly X-linked

Phosphorylase kinase Liver, skeletal muscle Hepatomegaly, short stature,

hy-potoniaPhosphorylase kinase Skeletal muscle Exercise intolerance, myoglobinu-

riaPhosphorylase kinase Heart Lethal infantile cardiomyopathy

Skeletal muscle Exercise-induced weakness,

myalgia, contractures, nuria

myoglobi-Muscle lactate

Myoclonus epilepsy (497) (p 512).

Generalized epilepsy, myoclonus, and

dementia are the characteristic

fea-tures of this autosomal recessive

dis-ease Its clinical signs include ataxia,

spasticity, rigidity, and dysarthria

The disease usually appears in

ado-lescence and then progresses

inexo-rably to death in early adulthood

Au-topsy reveals intraneuronal Lafora

bodies containing polyglucosans

Polyglucosan body disease (Fig 2.81).

This is a further disease in which

polyglucosans accumulate Patients

generally present in the fifth or sixth

decade of life with spasticity,

weak-ness due to involvement of the spinal

anterior horn cells, sphincter

distur-bances, sensory disturdistur-bances, and,

later, dementia (97d) This disease

may be confused at first with

amyo-trophic lateral sclerosis (p 434)

Disorders producing hypoglycemia.

As discussed below, intermittent

dis-turbances of carbohydrate

metabo-lism lead to systemic hypoglycemia

and its consequences for the brain (p

113) Disorders of glucose transport

from the plasma across the

blood-brain barrier into the neurons are

much rarer They are characterized by

intractable epileptic seizures that

first appear in early childhood and

take different forms depending on

the age of the patient (229a)

Cogni-tive and motor development are

slowed Low CSF concentrations of

glucose and lactate are essential to

the diagnosis

Treatment

A ketogenic diet can control the

sei-zures, but unfortunately does not

improve cognitive and motor

de-velopment

Disorders of Glycosylation

Carbohydrate-deficient glycoprotein syndrome (CDG syndrome) comprises

a group of multisystemic disordersdue to congenital defects of proteinglycosylation, resulting in the forma-tion of functionally deficent glycopro-teins The most common type is phos-phomannomutase deficiency (CDG-Ia), an autosomal recessive disordercharacterized initially by poor feedingand failure to thrive, and later by pys-chomotor retardation, pronouncedaxial hypotonia, muscle weakness,and cerebellar ataxia Seizures mayalso occur, and abnormalities of theglycoproteins involved in hemostasismay cause both hemorrhagic and is-chemic strokes and cerebral veousthrombosis Neuropathological exam-ination reveals olivopontocerebellaratrophy Patients surviving into ado-lescence and adulthood sometimesachieve some degree of social fun-tioning, but not independence

Diseases Whose Pathogenesis is Incompletely Understood

Alexander disease (124) This illness

appears in early childhood and ischaracterized by macrocephaly, spas-ticity, seizures, and dementia, pro-gressing within a few years to a vege-tative state and death It rarely arises

in adulthood, in which case it sents with dementia The histologicalfindings include Rosenthal fibers anddiffuse demyelination

pre-Schilder’s diffuse cerebral sclerosis

(encephalitis periaxialis diffusa) This

is a progressive leukoencephalopathymanifesting as progressive dementia,psychosis, corticospinal signs, andblindness, which may be the resulteither of optic neuritis or of cor-

tical lesions It is considered a variant

of multiple sclerosis (p 484 ff.) (766)

and its cause is unknown

Pelizaeus-Merzbacher disease

(chronic infantile cerebral sclerosis)

This disease, one of the sudanophilic

leukodystrophies, is inherited in an

autosomal recessive pattern and

pre-sents in the first few months or years

of life Its major features are tremor,

cerebellar ataxia, nystagmus, and,

later, paraparesis and dementia MRI

shows T2-hyperintensity of the white

matter (878)

Adrenoleukodystrophy (679) This

X-linked recessive heritable disorder is

due to a deficiency of lignoceroyl CoA

synthetase, an enzyme that is

neces-sary for the beta-oxidation of

long-chain fatty acids Boys are affected in

the first or second decade of life, at

first with mental changes, gait

distur-bance, visual impairment, and

dysar-thria, and later with progressive

quadriparesis In adult patients,

adre-nal insufficiency rather than

spasti-city may dominate the clinical

pic-ture Adrenomyeloneuropathy is a

form of the disorder in which there is

also a polyneuropathy A diagnostic

finding is an elevation of the serum

concentration of very-long-chain

fatty acids The progression of

neuro-logic impairment may be slowed by a

diet low in fatty acids and by bone

marrow transplantation The hope of

therapeutic benefit from “Lorenzo’s

oil,” which inspired a popular film of

the same name, has, unfortunately,

not been fulfilled (679)

Canavan’s disease This autosomal

re-cessive disorder becomes clinically

apparent in the first few months of

life A deficiency of enoyl CoA

hydra-tase impairs myelination and thus

causes developmental delay withblindness, hypotonia, spasticity, andmacrocephaly

Reye’s syndrome In 1963, Reye et al.

described a childhood encephalopathy with fatty infiltration of the viscera

(784) The syndrome is probably diated by mitochondrial dysfunction

me-of multifactorial cause (967) It pears a few days after a viral infectionand consists of persistent vomiting,somnolence, delirium, and coma.There is a statistically significant asso-ciation with the use of aspirin TheCSF is normal Imaging studies showcerebral edema, and the EEG revealsevidence of encephalopathy (slowingand triphasic waves) There is no spe-cific diagnostic test In the first fewyears after its original description,Reye’s syndrome was usually fatal;with current intensive-care methods,its mortality has been reduced to 30%

ap-Leigh syndrome This

neurodegenera-tive disease was described in 1951(569) It may already be manifest aslactic acidosis in the neonate, or itmay appear later with ataxia, flaccidweakness, hyporeflexia, ophthalmo-plegia, optic atrophy, and delayedgrowth and development MRI revealssymmetrical lesions resembling in-farcts in the basal ganglia, thalamus,and brainstem The serum and CSFconcentrations of pyruvate and lac-tate are elevated (825) Point muta-tions of mitochondrial DNA have beenfound in a few patients; thus, at leastsome patients with Leigh syndromesuffer from a mitochondrial encepha-lomyopathy (p 899) (235, 825)

Alipoproteinemias

Lipoproteins are needed for lipid

transport in the blood

Abetalipopro-teinemia (Bassen-Kornzweig disease)

results from a disorder of

apolipopro-tein B synthesis The serum

choles-terol and triglyceride concentrations

are very low, and there is a deficiency

of lipophilic vitamins, particularly

vi-tamin E Just as in Friedreich’s ataxia,

this leads to a fat malabsorption

syn-drome, retinitis pigmentosa,

progres-sive ataxia, nystagmus,

ophthalmo-plegia, polyneuropathy, and

acantho-cytosis

Hypobetalipoproteinemia can also be

associated with an ataxic syndrome

and signs of polyneuropathy, but

without acanthocytosis (14)

Acan-thocytosis with normal serum

betali-poprotein concentration is seen in an

autosomal recessive disorder

charac-terized by glossal atrophy,

polyneu-ropathy, chorea, and elevated serum

creatine kinase concentration A

simi-lar constellation of findings, termed

chorea-acanthocytosis and

neuroa-canthocytosis (817), is typically

inher-ited in an autosomal dominant

pat-tern and is only rarely seen in isolated

cases; the genetic defect lies on

chro-mosome 9q21 In Tangier disease, the

serum cholesterol concentration is

low, but the serum triglyceride

con-centration is normal The major

find-ings are massive enlargement of the

tonsils, hepatosplenomegaly, a

fluc-tuating, asymmetric polyneuropathy,

and, frequently, eyelid ptosis and

The prevalence of this

autosomal-recessive disorder of copper

metabo-lism is ca one in 30,000, ing to a frequency of the causative al-lele of ca one in 140-200 The af-fected gene, on chromosome 13q14.3,encodes a copper-transportingATPase The defect causes an abnor-mally low plasma concentration ofthe copper-transport protein cerulo-plasmin, which, in turn, results in anincrease in urinary copper excretionand toxic accumulation of copper inthe liver, brain, and other organs Un-bound (“free”) copper is present inthe plasma in an elevated concentra-tion

ab-Any of these may be the predominant

or even sole manifestation of the ease

dis-In cases of childhood onset, the initial

manifestation is usually either liver failure or hemolytic anemia, while

cases arising during adolescence orearly adulthood more commonly pre-sent with neurologic or psychiatricabnormalities

Neurologic and psychiatric ities, if present, are always accompa-nied by copper deposition in Desce-met’s membrane, externally visible as

abnormal-a brown discolorabnormal-ation of the edge ofthe cornea, the so-called Kayser-Fleischer ring (300), which is some-times detectable only by slit-lamp ex-amination The neurologic abnormal-ity is usually a movement disorder, ofwhich the more common manifesta-

tions are dysarthria, dysphagia, nia, and rigidity (of extrapyramidal

dysto-type) Less commonly, tremor may

af-fect the head, trunk, or limbs and is

typically a coarse postural and

inten-tion tremor, often called “flapping” or

“rubral” tremor (The older term

“pseudosclerosis” for

hepatolenticu-lar degeneration refers to the possible

misdiagnosis of the tremor as a

mani-festation of multiple sclerosis.)

Spas-ticity is rare, and sensory

distur-bances practically nonexistent

Epi-leptic seizures are seen in occasional

cases

The psychiatric manifestations of

he-patolenticular disease include

emo-tional lability, personality changes,

depression, and psychosis

Diagnostic Evaluation

MRI reveals signal abnormalities in

the basal ganglia CT and MRI are

usu-ally normal in the presymptomatic

stage of the disease, and thus cannot

be used as a screening test

Hepatolenticular degeneration

should be suspected in any child or

adolescent with liver failure,

hemo-lytic anemia, a movement disorder, or

a mental disturbance The diagnosis

is established by the measurement of

a serum ceruloplasmin concentration

below 200 mg/L and the observation

of a Kayser-Fleischer ring Most

pa-tients, whether symptomatic or

pre-symptomatic, will also be found to

have an excessive elimination of

cop-per in the urine (more than 100 ‘ g

per day) and an elevation of the free

serum copper concentration In

doubtful cases, the diagnosis can be

established by liver biopsy for

histo-pathologic examination, including

determination of copper content

Asymptomatic relatives of patients

suffering from the disease should be

screened for it by measurement of

the serum ceruloplasmin

concentra-tion and urinary copper eliminaconcentra-tion,

so that early treatment can be vided and the development of overtdisease prevented

pro-Treatment

The goal of treatment is the moval of the accumulated, toxiccopper deposits from the tissues ofthe body In the first 6–24 months

re-of treatment, this is done by ministration of the copper chelator

ad-d -penicillamine at a dose of 1 g/day,

or, in children under 10 years ofage, 0.5 g/day Patients must con-

currently take pyridoxine (vitamin

B6), at a dose of 25 mg/day, to teract the anti-pyridoxine effect ofd-penicillamine A hypersensitivityreaction consisting of fever, lymph-adenopathy, rash, leukopenia, andthrombocytopenia, may appearjust after the onset of treatment.Such reactions should not be mis-taken for the leukopenia andthrombocytopenia that are some-times a component of the diseaseitself

coun-d-penicillamine may also induce alupus-like syndrome or a myas-thenic syndrome Such cases are

treated with a combination of ethylenetetramine and tetrathiomo- lybdate, two other chelating agents

tri-that promote elimination of copper

in the urine (834)

Zinc sulfate and potassium sulfide

counteract the absorption of per in the intestine (431) Zinc sul-fate is currently the standard agentboth for maintenance treatmentand for treatment in the presymp-tomatic phase Treatment must becontinued for the life of the patient,and its discontinuation confers ahigh risk of death

cop-| Menkes’ Kinky Hair Syndrome

This X-linked recessive disturbance of

copper metabolism causes

abnor-mally low concentrations of

cerulo-plasmin in the plasma and of copper

in the tissues, and an impairment of

intestinal copper absorption (660)

Seizures, cognitive impairment,

blindness, hyperthermia, and

distur-bances of bone appear in the first few

months of life Kinky hair is a

charac-teristic associated finding

Mitochondrial

Encephalomyopathies (235, 467)

Disorders of mitochondrial function

that cause both encephalopathy and

myopathy are discussed below on p

usu-or chusu-orea leading to premature death.Other diseases associated with basalganglionic calcification include vari-ous forms of mitochondrial encepha-lomyopathy (p 902), and pseudohy-perparathyroidism (p 318) Calcifica-tion anywhere in the brain is alwayshyperdense on CT, and, in most cases,hypointense on T1- or T2-weighted

MR images Basal ganglionic tion is an exception to the latter rule:

calcifica-it tends to be hyperintense on weighted images, and hypo- or hyper-intense on T2-weighted images (48)

T1-Systemic Diseases Affecting the Nervous System (27)

Overview

Neurologic signs and symptoms may be the most prominent or sole festations of systemic disease Their recognition may provide the key to ac-curate diagnosis and effective treatment This section concerns systemicdiseases with major neurologic manifestations

mani-Toxic and Iatrogenic Conditions (623, 741, 768, 785)

Introduction

Toxic substances (especially medications) and medical procedures mayproduce neurologic abnormalities resembling those of primary neurologicdisease and distinguishable from them only by the history of the causativeevent Such abnormalities may be either subjective (e.g., headache) or ob-jective (cognitive impairment, cerebellar ataxia, extrapyramidal move-ment disorders, etc.) and are usually reversible, unless they reflect an un-derlying anatomic injury Thus, permanent damage is rare after drug-induced seizures, but common after drug-induced (or other iatrogenic)hemorrhage or ischemic stroke

The multifarious neurologic signs and

symptoms of intoxication may closely

resemble those of primary neurologic

disease, but a physician alert to the

possibility of intoxication can usually

make the diagnosis from a pertinenthistory Neurologic conditions thatmay be caused by intoxications of

various types are listed in Table 2.73.

This list is, necessarily, incomplete

Table 2.73 Neurologic manifestations of toxic or iatrogenic origin

Headache Nearly all headache preparations; withdrawal of caffeine,

ergotamine, or amphetamine; oral contraceptives andother hormone preparations (pseudotumor cerebri);nitrates, aminophylline, tetracycline, sympathomimetics, i.v.immunoglobulins, tamoxifen, H2-antagonists, dipyridamole,interferon

Ischemic stroke Oral contraceptives and other hormone preparations (413),

antihypertensive agents, ergotamine, amphetamine, caine, sympathomimetics, i.v immunoglobulins, intra-arterial methotrexate, angiography, interventional intra-arterial procedures, cardiovascular surgery, radiotherapy, fatinjection (“liposculpturing”) (269), steroid injections intothe nasal mucosa (269), chiropractic manipulation

ag-Seizures (664) Antibiotics (penicillin, isoniazid), general and local

anesthet-ics (e.g., lidocaine), insulin, radiological contrast media,withdrawal of benzodiazepines or other sedatives,anticonvulsant withdrawal, phenytoin overdose, antidepres-sants, aminophylline and theophylline, phenothiazines, pen-tazocine, tripelennamine, cocaine, meperidine, cyclospor-ine, antineoplastic agents, other

Coma (pp 221 ff.) Insulin, barbiturates, benzodiazepines and other sedatives,

butyrophe-(Cont.) 1

Table 2.73 (Cont.)

Cerebellar ataxia Phenytoin, carbamazepine, barbiturates, lithium, organic

solvents, heavy metals, acrylamide, 5-fluorouracil, cytosinearabinoside, procarbazine, hexamethylmelamine, vincris-tine, cyclosporine, ciguatera poisoning

Optic neuropathy Tobacco, ethanol, methanol, ethambutol (p 582)

Disorders of

neuro-muscular transmission Penicillamine, muscle relaxants, procainamide, magne-sium, quinine, aminoglycosides, interferon-alpha (p 911)

Myopathy and

rhabdomyolysis Ethanol, cocaine, heroin and other opiates, pentazocine,benzene, corticosteroids, thyroxine, antimalarial agents,

colchicine, antilipid agents (fibrates and statins), dine, cyclosporine, diuretics (via hypocalcemia), ipecacPhysicians confronted with a case

zidovu-that may be of this type should

con-sult the current version of a reference

work or web site that is regularly

up-dated for this purpose

| Acute and Chronic

Encephalopathies

Encephalopathy caused by

medica-tions, drugs of abuse, or toxic

indus-trial products usually manifests itself

in delirium, tremor, myoclonus,

aste-rixis, ataxia, seizures, or a

combina-tion of these In excepcombina-tional cases, an

extrapyramidal movement disorder

or cerebellar ataxia may be the most

prominent finding

Before these overt neurologic signs

develop, most patients go through a

“neurasthenic phase” characterized

by impaired psychomotor mance, deficits of attention and con-centration, headache, fatigue, insom-nia, vivid dreams and nightmares,dys- or euphoria, restlessness, irrita-bility, photo- and phonophobia, dizzi-ness, paresthesiae, and loss of sexualinterest

perfor-The elderly, in particular, may react tomedications usually thought harm-less with behavioral and cognitivedisturbances, including perceptual il-lusions and hallucinations

| Heavy Metal Intoxication (559) Mercury Chronic exposure to mer-

cury vapor or to mercury contained inorganic compounds, e.g in pesticides

or industrial waste products, causes

both gastrointestinal and neurologic

disturbances (620, 990) The former

include gingivitis, stomatitis,

exces-sive salivation, anorexia, and

abdomi-nal pain The latter include a fine

tremor (beginning in the hands,

tongue, and perioral region, later

spreading to the head and legs),

dys-arthria, dysphagia, and sometimes

ataxia, combined with a neurasthenic

syndrome (anxiety, irritability) and,

rarely, psychotic manifestations,

pa-resthesiae around the mouth and in

the extremities, and paresis Muscle

atrophy, fasciculations, and

pyrami-dal tract signs are occasionally

pre-sent (4)

Treatment

Penicillamine, which promotes the

renal excretion of urine, may be

used to treat chronic mercury

in-toxication

The clinical features of mercury

in-toxication are summarized in

Ta-ble 2.74.

Lead Lead poisoning has many

causes, such as the use (formerly) of

lead-containing ceramic dishes, or

chronic exposure in the

lead-processing industry It causes an

en-cephalopathy with cerebral edema, as

well as a polyneuropathy mainly

af-fecting extensor muscles, which may

Table 2.74 Manifestations of mercury

On examination, the characteristicgingival lead line may be seen Lum-bar puncture reveals an elevation ofthe CSF pressure and of the CSF pro-tein concentration There is baso-philic spotting of the erythrocytes,the serum lead level exceeds 0.5 ‘ g/L,the concentrations of hemoglobinprecursors such as delta-amino-levulinic acid are elevated in serumand urine (G 20 mg/dL), and the uri-nary coproporphyrin excretion is ele-vated (G 150 mg/24 h) The clinicalfeatures of lead intoxication are sum-

marized in Table 2.75.

Treatment

Lead intoxication is treated withchelators such as dimercaprol (BAL), ethylene diamine tetra-acetic acid (EDTA), penicillamine, and (in children) succimer (678).

Table 2.75 Manifestations of lead

poison-ingSigns of intracranial hypertensionOptic atrophy

SeizuresDeliriumPolyneuropathy, esp hand dropColic

Lead ring

Bismuth salts Bismuth salts are used

to treat various gastrointestinal

dis-turbances (481) Bismuth intoxication

is manifest as a neurasthenic

pro-drome consisting of impaired

psycho-motor performance, deficits of

atten-tion and concentraatten-tion, headache,

in-somnia, and anxiety, followed by

muscle twitching and an impairment

of balance and coordination If the

in-toxication is not promptly diagnosed

and treated in this phase, it

progres-ses to acute encephalopathy, with

de-lirium, myoclonus, severe ataxia, and

variable impairment of

conscious-ness, ranging from mild confusion to

coma (631) Abdominal radiographs

reveal bismuth in the intestine The

diagnosis is confirmed by the

demon-stration of bismuth in the urine,

se-rum, or cerebrospinal fluid The

clini-cal features of bismuth intoxication

are summarized in Table 2.76.

Treatment

Dimercaprol (BAL) is beneficial, and

the long-term prognosis is good

once bismuth salts have been

dis-continued

Other heavy metals Arsenic,

thal-lium, manganese, and zinc cause

clin-ically similar forms of

encephalopa-thy; arsenic and thallium also cause

polyneuropathy (p 610) Thallium

sometimes causes subacute

myelopa-thy and optic neuropamyelopa-thy (p 625)

(79) Manganese poisoning is

typi-cally manifest as parkinsonism, more

rarely as chorea (pp 245 and 261)

| Intoxication with Organic

Solvents and Other Industrial

Products

The most important organic solvents

are carbon disulfide, n-hexane,

meth-Table 2.76 Manifestations of bismuth

poisoningNeurasthenic prodromeDelirium

Gait ataxia, limb ataxiaDysarthria

Myoclonus

ylbutylketone, perchlorethylene, chloroethylene, and toluene Thesehighly lipid-soluble agents, widelyused in the home, in the hobbyist’sworkshop, and in industry as sol-vents, diluents, and cleaning and de-fatting agents, pose a danger to thecentral and peripheral nervous sys-tems They are highly volatile andtheir vapors are easily inhaled, eitheraccidentally or intentionally (gluesniffing) They generally have non-specific sedative or anesthetic effects

tri-Acute exposure tri-Acute exposure to

organic solvents leads to athy, manifesting itself through cog-nitive impairment, confusion, dyse-quilibrium, tinnitus, paresthesiae,ataxia, weakness, headache, nausea,and vomiting, and, in more severecases, impaired consciousness rang-ing to coma Once the exposure is ter-minated, recovery in minutes tohours is the rule, though headachemay persist thereafter for a few hours

encephalop-or even days

Chronic exposure Depending on its

severity and duration, chronic sure to organic solvents causes either

expo-a neurexpo-asthenic syndrome or toxic cephalopathy with cognitive impair-ment, insomnia, delirium, and amovement disorder Nystagmus and

en-ataxia are the most consistent,

objec-tive neurologic signs There is,

how-ever, some controversy as to whether

a chronic encephalopathy with

cogni-tive deficits exists in some

occupa-tional groups, e.g., painters

Long-standing, repeated exposure to

cer-tain types of organic solvents, such as

trichloroethylene, n-hexane, and

other hexacarbons, may cause axonal

polyneuropathy (p 612)

Toluene Toluene causes

psycho-organic changes of variable severity,

up to overt dementia, as well as

cere-bellar, brainstem, and pyramidal tract

signs and cranial nerve deficits (482)

These disturbances tend to be severe

in persons who sniff toluene

deliber-ately for its intoxicating effect, in

whom MRI may reveal brain atrophy

and white matter changes (434)

Methanol Methanol, when

acciden-tally or intentionally drunk in place of

ethanol, causes a frequently lethal

metabolic acidosis with acute

en-cephalopathy and optic neuropathy

(873) Methyl acetate, which is

metab-olized to methanol, and methyl

for-mate can also cause optic neuropathy.

Nitrous oxide Nitrous oxide abuse

can cause myeloneuropathy with

spastic paraparesis, sensory ataxia,

and sphincter disturbances (102,

558)

Carbon monoxide Acute carbon

monoxide poisoning causes hypoxic

injury to the central nervous system,

potentially resulting in coma or

death Autopsy reveals diffuse neuron

loss in the cerebral cortex and

bilat-eral necrosis of the globus pallidus

Survivors may have severe cognitive

deficits, spasticity, and parkinsonism(p 245)

Other industrial products In

princi-ple, nearly any gas that is present insufficiently high concentration cancause acute encephalopathy and hyp-

oxic brain damage Ethylene oxide,

used to sterilize surgical instruments,can cause central nervous systemdamage and polyneuropathy (197)

Acrylamide causes acute

encephalo-pathy, as well as polyneuropathy afterchronic exposure

| Organophosphate (Pesticide)

Intoxication (863)

Organophosphates are used as ticide and rodent poison, and as aweapon in chemical warfare; one par-

insec-ticular kind, triorthocresyl phosphate,

is used as an additive to industrialoils They inhibit acetylcholinesterase

in the central nervous system and the

“neuropathy target esterase” in theperipheral nervous system, causingsynaptic depolarization block.Intoxication causes bronchospasm,excessive salivation, diarrhea, miosis,impaired pupillary accommodation,fasciculations, behavioral distur-bances, anxiety, agitation, delirium,seizures, and paralysis Respiratoryparalysis may be lethal, and atropine

is life-saving (432) Surviving patientsdevelop polyneuropathy 1–3 weekslater, followed by spasticity andataxia (for a further discussion of tri-orthocresyl phosphate and triarylphosphate poisoning, see p 611).Chronic exposure may also impairmemory (487) If organophosphaterodent poison is eaten, perhaps withsuicidal intent, coma ensues, with op-soclonus, myoclonus, and flaccid pa-resis, which later converts, if the pa-tient survives, to spasticity

| Medications

Various medications may cause

en-cephalopathy with cognitive

impair-ment, delirium, extrapyramidal or

cerebellar movement disorders, or

seizures, usually on a

dose-dependent basis These include

anti-convulsants, corticosteroids,

dopami-nergic agonists, cimetidine, isoniazid,

monoamine oxidase inhibitors,

pen-tazocine, propoxyphene,

cyclospor-ine, interferon, methotrexate,

vincris-tine, and other cytostatic agents

Water-soluble contrast agents used in

myelography, such as metrizamide,

may cause acute encephalopathy and

seizures Hypoglycemia caused by an

overdose of insulin can produce

en-cephalopathy, as can iatrogenic

SIADH with hyponatremia (see p

334 f.) Penicillin rarely causes an

en-cephalopathy that manifests itself

through myoclonus, seizures, and

im-pairment of consciousness

| Cerebellar Ataxia Caused By

Medications and Other

Substances

Anticonvulsant overdoses (e.g., of

phenytoin, carbamazepine, or

barbi-turates) can cause an encephalopathy

mainly affecting the cerebellum,

characterized subjectively by

dizzi-ness and imbalance, and objectively

by end-gaze nystagmus, dysarthria,

Table 2.77 Manifestations of phenytoin

ataxia, and gait impairment ranging

to astasia-abasia Prompt recognition

of phenytoin intoxication is important,

because, if unchecked, it may lead toirreversible ataxia (862) Phenytoinalso causes gingival hypertrophy andpolyneuropathy, though the latter is

usually subclinical (767) (Table 2.77).

The ordering physician should beaware that the pharmacokinetics ofphenytoin predispose to overdose:the serum concentration of the drugrises exponentially in relation to thedosage

Lithium intoxication, too, causes a

pri-marily cerebellar encephalopathy.Two-thirds of patients receiving lith-ium at therapeutic doses developmild tremor and cog-wheel rigidity,and diabetes insipidus and weightgain are also common Severe, acuteencephalopathy (ataxia, rigidity, hy-pokinesia, mutism, seizures, coma)and polyneuropathy are rare (240,739)

Ataxia may also result from

treat-ment with cytostatic agents including

5-fluorouracil, cytosine arabinoside,procarbazine, hexamethylmelamine,and vincristine, and the immunosup-

pressive agent cyclosporine (768).

Ataxia may also be the most nent sign of encephalopathy caused

promi-by organic solvent, heavy metal, oracrylamide poisoning Ciguatera fishpoisoning is characterized by acuteataxia and paresthesiae

Acute dystonia and dyskinesia

Neu-roleptics such as phenothiazines,

Table 2.78 Medication-induced

butyrophenones, and the antiemetic

metoclopramide may induce acute

dystonia and dyskinesia, usually

lim-ited to the muscles of the head and

neck and consisting of grimacing,

trismus, abnormal movements of the

tongue, dysphonia, orofacial

dyskine-sia, oculogyric crises, or torticollis

and retrocollis Generalized forms

af-fecting the muscles of the trunk and

limbs are less common Physicians

unaware of the possibility of acute

iatrogenic dystonia and dyskinesia

may misdiagnose them as hysteria

Intravenously administered

anticho-linergics (e.g., 10–20 mg of biperiden)

usually bring immediate relief

Akathisia This term refers to a state

of motor unrest (literally, the inability

to sit still) (50, 553), which is to be

distinguished from restless legs

syn-drome (p 845) Affected patients feel

an irresistible inner urge to move

Akathisia may be a side effect of

anti-psychotics (phenothiazines and

buty-rophenones), antiemetics, and

dopa-minergic agonists

Medication-induced parkinsonism.

Antipsychotic medications, pertensives (e.g reserpine, captopril),flunarizine and cinnarizine, MPTP,and other substances may induce par-kinsonism that is distinguishablefrom idiopathic Parkinson’s diseaseonly by history (p 245) It usually re-gresses after a few weeks or monthsand may be treated in the meantimewith antiparkinsonian medication, ifnecessary

antihy-Other movement disorders The

pro-longed use of antipsychotic

dopami-nergic antagonists may induce late (“tardive”) dyskinesia and dystonia

(153, 945), which appear either ing the course of drug treatment orimmediately after discontinuation orreduction of the dose Their patho-physiology is not entirely clear; it isassumed that long-term use of anti-dopamine agents causes either de-nervation hypersensitivity of the stri-atal dopamine receptors or a loss ofGABA-mediated thalamocortical inhi-bition (Involuntary movements alsofrequently complicate the long-termuse of levodopa in patients with Par-kinson’s disease; cf p 247) Tardivemovement disorders may be of prac-tically any kind The most common

dur-variety is the buccolinguomasticatory syndrome, with stereotypic chewing,

licking, and smacking movements, sembling those seen in Meige syn-drome (p 268) Dyskinesia and dysto-nia may also affect the extremities,however, e.g as dystonia of the toes

re-or as an appendicular tremre-or, tardivemyoclonus, tic disorder, or even iatro-genic pseudo-Gilles de la Tourette

syndrome (519, 901; cf p 272) Pisa syndrome, involving lateral inclina-

tion and torsion of the trunk, neck,and head, is most commonly seen in

elderly patients after chronic

neuro-leptic use (548) (The odd, and

per-haps inappropriate, name is an

allu-sion to the Leaning Tower of Pisa.)

Most patients with tardive movement

disorders are unaware or barely

aware of them, but some find them

profoundly disturbing (605)

Treatment of Tardive

Movement Disorders

The first step is the removal of the

causative agent If the movement

disorder worsens, treatment

should then be begun with an

anti-cholinergic medication or a

benzo-diazepine Bothersome focal

dyski-nesias, such as blepharospasm, can

be treated with botulinum toxin.

Only if such measures fail should a

dopamine antagonist be tried, e.g.

tiapride, tetrabenazine, or

reser-pine These medications should not

be given indefinitely, but rather

slowly tapered, and then

discontin-ued

Once the causative agent is

re-moved, it may take months or even

years for the tardive movement

disorder to remit (520) Neuroleptic

medications should therefore be

prescribed sparingly and for no

longer than clinically necessary in

each case If antipsychotic

treat-ment must be continued in the face

of a potential, or actual, movement

disorder, then an agent with fewer

extrapyramidal side effects is

pref-erable (e.g clozapine)

Malignant neuroleptic syndrome

(371, 539, 763) The initial

adminis-tration of a neuroleptic agent, or an

increase in its dose, may cause

sweat-ing, tachycardia, and fluctuations of

blood pressure, followed by rigidity,

dystonia, and fever The serum centration of creatine kinase is dra-matically elevated Malignant neuro-leptic syndrome is often life-threatening; without treatment, itsmortality is ca 25%

con-Treatment

The neuroleptic agent is ued at once, fluid and electrolytesubstitution is given, and any med-ical complications, such as pulmo-nary embolus or pneumonia, are

discontin-treated Levodopa, dopaminergic agonists, and spasmolytics such as

dantrolene may shorten the tion of the syndrome (see also ma-lignant hyperthermia, p 900)

dura-| Alcohol and the Nervous

System

Table 2.79 provides an overview of

the effects of ethanol (ethyl alcohol,colloquially “alcohol”) on the nervoussystem (176, 979) The most commonlong-term complication of alcoholoveruse is polyneuropathy Genetic,metabolic, and environmental factorsaccount for the variable predisposi-tion to alcoholism among individuals,

as well as the multifarious forms thisaddiction can take

| Acute Alcohol Intoxication

Drunkenness expresses itself as phoria or dysphoria, complaisance oraggressiveness, diminished concen-tration, prolonged reaction times, andloss of interpersonal distance, includ-ing loss of sexual inhibition Furthersigns include slurred speech, ataxicgait, diplopia, nausea, dizziness,tachycardia, sudden outbursts of rage,and antisocial behavior, and, withvery high blood alcohol concentra-

eu-Table 2.79 Alcohol and the nervous system

Alcoholic cerebellar degeneration

Central pontine myelinolysis

Tobacco-alcohol amblyopia

Alcoholic polyneuropathy

Alcoholic myopathy

> Acute necrotizing myopathy

> Chronic myopathy, occasionally cardiomyopathy

Alcohol and stroke

Pachymeningeosis hemorrhagica interna

Fetal alcohol syndrome

Special features of alcoholism

> Dipsomania

> Alcohol-induced hypoglycemia

> Accidental intoxications with other substances: optic neuropathy due to methanolconsumption, lead encephalopathy in moonshine drinkers, etc

tions, somnolence, stupor, coma,

re-spiratory suppression, and death

| Alcohol Withdrawal, Alcoholic

Hallucinosis, Alcoholic Seizures

Alcohol withdrawal The declining

concentration of alcohol in the blood

after a single binge is accompanied by

a “hangover” consisting of headache,

dysphoria, tremulousness, and

sweating Morning tremulousness

improving with alcohol consumption,

nervousness, timidity, facial and

con-junctival erythema, sweating,

an-orexia, nausea, tachycardia,

tachyp-nea, and hypertension are signs of

longer-term overuse of alcohol (for at

least several days); they regress after

a few days of abstinence

Alcoholic hallucinosis Severe alcohol

abuse causes perceptual disturbances

including nightmares, illusions, and

hallucinations Illusions and

halluci-nations may be visual, auditory,

tac-tile, or olfactory, and often involve

(imaginary) animals or insects If they

last for more than a few minutes, a

true alcoholic hallucinosis with

para-noid psychotic features, or a

pre-delirium, may develop.

Alcoholic seizures Alcoholic seizures

(“rum fits”) may appear in the

pres-ence or abspres-ence of alcoholic

halluci-nosis and are usually generalized, but

sometimes focal Alcohol may be the

factor that induces the first seizure in

a patient with another underlying

cause of seizures; thus, seizures

oc-curring during alcohol use or alcohol

withdrawal still require diagnostic

evaluation

| Delirium Tremens

Delirium tremens is heralded by anepileptic seizure in 10% of cases, typi-cally 2–3 days after the cessation ofalcohol consumption Patients withdelirium tremens are disoriented,sleepless, anxious, and agitated, fum-ble with the bedclothes, and sufferfrom perceptual illusions and halluci-nations, usually involving animals(particularly rodents) or insects Theyoften experience these illusions andhallucinations as threatening, andmay make violent efforts to “defendthemselves.” They are highly suggest-ible and may, for example, start read-ing from a blank sheet of paper.Tremor, sweating, and tachycardia arecharacteristic findings

Seizures, if they occur, should alwaysprompt suspicion of another underly-ing cause besides alcohol withdrawal,e.g meningitis It is also not uncom-mon for delirium tremens itself (with

or without seizures) to be induced by

an intercurrent illness in an alcoholic.The prevention and treatment of al-coholic delirium are detailed in Ta-

ble 2.80 (418, 531, 820) Mild

with-drawal phenomena can be treated on

an ambulatory basis if home stances allow, but all patients with fe-ver, seizures, or hallucinations should

circum-be hospitalized Delirium tremens isfatal in 15% of cases if untreated

| Dementia in Various

Conditions Due to Alcohol Abuse

Alcoholic dementia Chronic alcohol

abuse causes cognitive deficits thatare largely reversible with absti-nence Histopathological study mayreveal neuronal loss and brain atro-phy

Table 2.80 Treatment of alcohol

with-drawal and alcoholic delirium

> Thiamine 100 mg i.m or i.v., and

multivitamin preparation

> Diazepam (Valium) 10–40 mg p.o or

i.v., or chlordiazepoxide (Librium)

25–200 mg p.o or i.v.,

or

Clomethiazole (Distraneurin) 0.6–1.2 g

p.o or 0.8% solution i.v., initially

24–60 mg/min, then 4–8 mg/min;

the initial dose should be high

enough to produce sedation

Repeat every 1–4 hours, reduce dose

by 25% daily (Note: not available in

USA)

> Fluid replacement with sufficient

glu-cose, potassium, calcium,

magne-sium, phosphate

> Treatment of seizures due to alcohol

withdrawal with phenytoin, initially

500–1000 mg i.v., then 300 mg/d for

1–3 weeks (should not be given

in-definitely)

> Treatment of any accompanying

ill-nesses (meningitis, subdural

hema-toma, variceal bleeding, pancreatitis,

etc.)

Korsakoff’s amnestic syndrome and

Wernicke’s encephalopathy (388,

979) Both of these conditions are due

to thiamine deficiency and are

some-times caused by poor nutrition in

nonalcoholics, e.g in patients with

anorexia nervosa Korsakoff’s

syn-drome (p 388) consists of acute

ante-rograde and retante-rograde amnesia, with

confabulation Wernicke’s

encepha-lopathy is characterized by

oculomo-tor disturbances and ataxia in

addi-tion to the signs of Korsakoff’s

syn-drome The oculomotor disturbances

are bilateral and asymmetrical and

may consist of abducens palsy,

hori-zontal or rotatory nystagmus, and

conjugate gaze palsy or even total

ex-ternal ophthalmoplegia The lary reflexes may be slowed Dysar-thria, appendicular ataxia, and (mostprominently) truncal ataxia are usu-ally present; the patient may be un-able to stand or walk EEG usually re-veals slowing of the backgroundrhythm T2-weighted MR imagesshow abnormal signal intensity, andsometimes contrast enhancement, inthe periaqueductal region and adja-cent to the third ventricle (329), cor-responding to the histopathologicalfindings of neuron and axon loss, de-myelination, and small foci of hemor-rhage

pupil-Treatment

Thiamine (100 mg/d i.v or i.m.), multivitamins (particularly includ-

ing the vitamin B complex), and

glucose-electrolyte solutions aregiven acutely Glucose, however,should be given only after thiaminehas been given, as it may otherwiseinduce acute worsening of Wer-nicke’s encephalopathy

The syndrome regresses after ment, but there are often residualoculomotor disturbances, ataxia,and memory impairment

treat-Alcoholic cerebellar degeneration

(see Table 2.79) Prolonged alcohol

abuse (years) can lead to cerebellar atrophy, mainly affecting the vermis.

Its major clinical manifestation isataxia of the limbs (mainly the legs),

as opposed to the truncal ataxia seen

cen-origin and is characterized by highly

symmetrical demyelination in the

corpus callosum, the centrum

semi-ovale, and other white matter areas It

is clinically expressed by acute

confu-sion, seizures, and impairment of

consciousness Surviving patients are

usually permanently abulic and

de-mented Before the advent of MRI,

this condition could only be reliably

diagnosed at autopsy

Hepatocerebral degeneration and

pellagra Hepatocerebral degeneration

and pellagra are further causes of

dementia in alcoholics The former is

a consequence of long-standing,

chronic portocaval encephalopathy

(p 342), the latter of niacin or

trypto-phan deficiency Pellagra is

charactized by glossitis, diarrhea, anemia,

er-ythematous changes in exposed areas

of the skin, and encephalopathy

lead-ing to dementia In industrialized

countries, this condition is rare even

among alcoholics, because the

en-richment of grain with niacin is

man-dated by law

| Other Conditions Due to

Alcohol Abuse (see Table 2.79)

Alcoholic hypoglycemia (p 313) is due

to an alcohol-induced disturbance of

gluconeogenesis Dipsomania is an

unquenchable craving for alcohol that

usually arises episodically and is

as-sociated with phases of unusually

high alcohol consumption, which

may cause lasting somatic damage

Alcoholics are also at elevated risk of

ischemic and hemorrhagic stroke (p.

210) Finally, grievous harm may

re-sult if methanol (p 304), ethylene

glycol, or other neurotoxic substances

are consumed by accident instead of

ethanol

| Drugs of Abuse and the

Nervous System (149)

Drug abuse may lead to physical and

psychological dependence and

addic-tion (see Table 2.81 for a list of the

more commonly abused drugs)

Table 2.81 The most commonly abused

> LSD

> “Ecstasy” (= methylenedioxymethamphetamine,MDMA)

3,4-> Psilocybin

Inhaled (“sniffed”) substances:

Solvents, gasoline; glue or paint taining toluene, n-hexane, aliphatic hy-drocarbons, nitrous oxide, trichloroeth-ylene, etc

con-Phencyclidine (“angel dust”) Anticholinergics

Ethanol Tobacco

Withdrawal may produce an extreme

craving for the drug and somatic

ef-fects such as nervousness, tremor,

sweating, and tachycardia

Effects on the nervous system Most

drugs of abuse cause a pleasant state

of altered consciousness with

disinhi-bition, euphoria, or

depersonaliza-tion, which may, however, rapidly

convert into a state involving

unde-sired illusions, hallucinations,

para-noid psychosis, or depression Motor

hyperactivity normally accompanies

this state altered of consciousness

when some of these drugs are used A

drug overdose can cause nystagmus,

ataxia, myoclonus, hypothermia,

an-algesia, hypertension, orthostatic

hy-potension, respiratory depression,

and impaired consciousness ranging

to coma Drug withdrawal usually

causes nausea, vomiting, abdominal

cramps, loss of appetite, headache,

sweating, skin erythema, tremor,

tachycardia, cardiac dysrhythmia,

fe-ver, seizures, or “flashbacks” (intense

reliving of past experiences)

Bodily harm directly or indirectly due

to drug abuse Drug abusers are

prone to bodily harm of many

differ-ent kinds Acciddiffer-ents, e.g those caused

by drunk or otherwise intoxicated

drivers, and suicide are major risks

as-sociated with drug abuse

Intrave-nous drug abuse predisposes to

infec-tions of many different kinds (local

infections, hepatitis, AIDS,

endocardi-tis, tetanus, mycotic cerebral

aneu-rysms) Ischemic and hemorrhagic

stroke are devastating complications

seen in abusers of alcohol, tobacco,

heroin, cocaine, pentazocine,

tripe-lennamine, amphetamine, LSD,

phen-cyclidine, and ecstasy Drug-induced

coma with respiratory depression

may lead to permanent anoxic injury

to the brain and other organs (485,

576, 887) Rhabdomyolysis and quent renal failure are known compli-

conse-cations of heroin, amphetamine,

co-caine, and phencyclidine abuse mentia may be the ultimate result of

De-long-term alcohol abuse or a quence of addiction-related malnu-trition, head trauma, ischemic andhemorrhagic strokes, and brain infec-tions Various substances, particularly

conse-solvents, can cause polyneuropathy.

Heroin injection by addicts has been

reported to cause lumbar and brachial plexopathy as well as Guillain-Barr´e syndrome, presumably through an au- toimmune mechanism Pressure neu- ropathies and plexopathies often re-

sult from the lack of shifting ments during drug-induced stuporand coma, in distinction to normalsleep (e.g., the well-known “Saturdaynight palsy” of the radial nerve) Fi-

move-nally, MPTP (p 245) causes sonism, and the smoking of heroin pyrolysate causes leukoencephalopa- thy (444).

parkin-Treatment

Acute opioid or benzodiazepine toxication can be treated with therespective receptor antagonists,

in-naloxone (Narcan) and flumazenil (Romazicon) General supportive

care is given to maintain fluid andelectrolyte homeostasis and pre-vent complicating conditions (seeabove discussion) Such conditions,

if already present, will require cific treatment

spe-Endocrine Disorders with Neurologic Manifestations

Overview:

Endocrine disorders cause metabolic derangements that, in turn, give rise

to metabolic encephalopathy, which may manifest itself in an impairment

of cognitive function, alteration of consciousness, or both They can alsocause myopathy and peripheral neuropathy of various types

| Hypoglycemia (313,610)

Glucose is, for all practical purposes,

the exclusive energy source for

cere-bral metabolism If the plasma

glu-cose concentration falls below a

criti-cal level, the CNS and autonomic

ner-vous system can no longer function

normally The more important causes

of hypoglycemia are listed in

Ta-ble 2.82 Hypoglycemia can arise

postprandially as well as after a

pro-longed fast

Clinical Features

The manifestations of hypoglycemia

(Table 2.83) are independent of its

etiology They may last only a few

minutes, or for hours or longer

Auto-nomic disturbances usually appear

first, followed by central nervous

dis-turbances The autonomic

manifesta-tions include dizziness, sweating,

nausea, pallor, palpitations, a

precor-dial pressure-like sensation,

abdomi-nal pain, hunger, anxiety, and

head-ache; the central nervous

manifesta-tions include seizures, impairment of

consciousness, and focal neurologic

deficits

Thus, the initial stage of

hypoglyce-mia usually consists of paresthesiae,

cloudy or double vision, tremor, and

abnormal behavior; focal neurologic

deficits and seizures follow, with

im-pairment of consciousness The

neu-rologic deficits may be of any

con-ceivable type; acute hemiparesis is

the most common Seizures may be

simple partial, complex partial, orgeneralized, and consciousness may

be impaired to any extent from nolence to deep coma

som-Table 2.82 Causes of hypoglycemia Postprandial (reactive) hypoglycemia:

Hepatopathy Medications and drugs of abuse:

> Systemic carnitine deficiency

> Lipid oxidation disorders

> Cachexia with fat depletion

Table 2.83 Clinical manifestations of hypoglycemia

Central nervous manifestations:

> Paresthesiae, clouded vision, diplopia, tremor, unusual or abnormal behavior

> Seizures (simple partial, complex partial, generalized)

> Impairment of consciousness ranging form somnolence to coma

> Focal neurologic deficits – e.g., hemiparesis, hemianopsia, aphasia, apraxia

Permanent neurologic injury:

> Cognitive deficits, dementia

> Specific cognitive deficits, focal neurologic deficits

> Predominantly distal muscle atrophy (damage of the anterior horn cells and theiraxons)

Diagnostic Evaluation

The nonspecific EEG changes include

diffuse and focal slowing and

tri-phasic waves

The diagnosis is based on a low

serum glucose concentration

( X 2.5 mmol/L) measured during the

clinical event Repeated postprandial

hypoglycemia can be diagnosed with

the aid of a glucose tolerance test,

fast-ing hypoglycemia with a fastfast-ing test

or elevated insulin concentration

Permanent Neurological Injury from

Recurrent Hypoglycemia

Hypoglycemia is a deficiency of the

key metabolic substrate of the neuron

and thus leads to neuronal injury

Re-current hypoglycemia causes a

de-cline in cognitive ability that may be

severe enough to qualify as

demen-tia; it may also cause lasting focal

neurologic disturbances such as

aphasia, apraxia, hemianopsia, or miparesis, which may be more read-ily apparent than the cognitive im-pairment Insulinomas that cause re-current, prolonged episodes of hypo-glycemia sometimes produce a so-called hypoglycemic neuropathy,which presumably reflects injury tothe anterior horn cells and their ax-ons It clinically resembles a predom-inantly distal form of spinal muscularatrophy (459)

he-| Hyperglycemia Clinical Features

Hyperglycemia is almost always due

to diabetes mellitus It can produce ametabolic encephalopathy of variableseverity, ranging to coma There aretwo forms of hyperglycemic coma:

> ketoacidotic coma and

> hyperosmolar diabetic coma

Diabetic ketoacidosis This syndrome

is encountered in insulin-dependent

diabetics and is characterized by an

impairment of consciousness with

Kussmaul respiration The

extracellu-lar volume deficit is less than that of

hyperosmolar coma

Hyperosmolar, nonketotic diabetic

coma This syndrome is typically seen

in non-insulin-dependent diabetics

in whom a hyperglycemic diuresis

has led to extracellular volume loss If

the patient does not drink enough

fluid to compensate for this, a severe

volume deficiency with

hyperosmo-larity results (p 336)

Diagnostic Evaluation

The diagnosis is based on the

demon-stration of glucose and ketones in the

urine, and of hyperglycemia,

meta-bolic acidosis, and an anion gap in the

serum Lactic acidosis, uremia,

alco-holic ketoacidosis, and a number of

intoxications may produce a similar

picture

Treatment

The treatment of diabetic

ketoaci-dosis consists of insulin

administra-tion and fluid replacement (usually

3–5 liters), potassium, and

bicar-bonate.

In hyperosmolar, nonketotic coma,

the serum glucose concentration is

usually higher than in diabetic

ke-toacidosis, and the acidosis is

usu-ally only mild The treatment

re-quires larger volumes of fluid (as

much as 10 liters), as well as

insu-lin, potassium, and (if acidosis is

present) bicarbonate

| Hypothyroidism (927) Clinical Features

A deficiency of thyroid hormone in utero or during infancy leads to cre- tinism; childhood hypothyroidism causes stunted growth and mental re- tardation Hypothyroid adolescents

and adults suffer from a wide variety

of disturbances affecting the CNS,PNS, and muscles The neurologicmanifestations are largely indepen-dent of the etiology of hypothyroid-ism

General manifestations

Hypothy-roidism is characterized by slowlyprogressive lethargy, fatigue, consti-pation, and cold intolerance

Neurologic manifestations The

neu-rologic manifestations of

hypothy-roidism include (Table 2.84):

> Headache, rarely pseudotumor rebri

ce-> An axonal polyneuropathy (657) (p.614) is seen in 80% of chronicallyhypothyroid individuals, present-ing with marked paresthesiae and

a sensory deficit along with a dency toward compression neu-ropathies such as carpal tunnelsyndrome

ten-> Cranial nerve deficits rarely caused

by hypothyroidism include tus, hearing loss, vertigo, ptosis,hoarseness (due to infiltration ofthe vocal folds with mucopolysac-charides), and facial pain

tinni-> Myopathy (p 914) (830, 929, 975,1029) is common in hypothyroid-ism, typically presenting with my-algia and a feeling of stiffness.Some 30–40% of patients developmyopathic weakness, which usu-ally involves the pelvic muscles andthe proximal muscles of the lower

limbs, less often the proximal

mus-cles of the upper limbs and the

dis-tal muscles of all the limbs

Hypo-reflexia is most easily observed at

the ankles Tapping a muscle may

produce a visible bump

(myoe-dema) Disturbances of

neuromus-cular transmission, muscle

hyper-trophy, and myotonia are also

en-countered

> Cerebellar dysfunction is

occasion-ally clinicoccasion-ally prominent,

manifest-ing as dysequilibrium, ataxia,

im-paired coordination, dysarthria,

and nystagmus (378)

> Mental abnormalities include

apa-thy, impairment of attention,

con-centration, and memory, dementia,

depression, hallucinations, and

psychotic delirium, sometimes

leading to coma

> Seizures are a further feature of

hy-pothyroidism

Diagnostic Evaluation

CSF examination may reveal an

ele-vated protein concentration The EEG

is diffusely slowed and low in

ampli-tude The serum concentration of the

thyroid hormones fT3 and fT4 is low,

while that of TSH is elevated (except

in the rare case of a primary

defi-ciency of hypothalamic TSH

secre-tion)

Treatment

The treatment of hypothyroidism

generally requires lifelong thyroid

hormone supplementation.

| Hashimoto’s Thyroiditis

Encephalopathy with a high roid antibody titer in the setting ofHashimoto’s thyroiditis (869, 539a) is

antithy-a clinicantithy-al entity distinct from theusual form of hypothyroid encepha-lopathy It presents with confusion,impairment of consciousness, delir-ium, and focal and generalized sei-zures

> Headache

> Polyneuropathy (mainly sensory),carpal tunnel syndrome, cranialnerve deficits (rare)

> Myopathy, delayed relaxation of trinsic muscle reflexes, myxedema

in-> Ataxia and other cerebellar signs

> Behavioral and neuropsychologicalabnormalities, apathy, dementia, de-pression, psychotic delirium, coma

Thyrotoxicosis has similar

manifesta-tions whatever its etiology In Graves’

disease, hyperthyroidism is

accompa-nied by endocrine ophthalmopathy

General manifestations The general

manifestations of thyrotoxicosis

in-clude nervousness, insomnia, tremor,

diaphoresis, tachycardia, diarrhea,

and heat intolerance

Neurologic manifestations The

neu-rologic manifestations of

thyrotoxico-sis include (Table 2.85):

> Myopathy (465) predominantly

causes weakness of the pelvic and

proximal limb muscles, making it

difficult for the patient to rise from

a chair or raise the arms It may be

accompanied by myasthenia gravis

that worsens during a thyrotoxic

crisis, by an acute oculofaciobulbar

myopathy with dysarthria,

dyspha-gia, and ocular ptosis, or by

thyro-toxic periodic paralysis (p 914) As

in familial hypokalemic paralysis,

there are attacks of focal or

gener-alized weakness that may last for

minutes, hours, or days

Polyneu-ropathy is very rare

> CNS manifestations: the behavioral

abnormalities range from mild

irritability to psychosis (rare)

Tremor is practically always

pre-sent; it may be very fine, like a

catecholamine-induced tremor, or

– particularly in older patients –

coarse and of lower frequency, like

Table 2.85 Clinical manifestations of

> Thyrotoxic periodic paralysis

> Polyneuropathy (very rare)

> Decreased frequency of blinking

> Lid retraction (Graefe’s sign)

> Impaired convergence (Möbius’s sign)

an essential tremor (p 270)

Chore-oathetosis, spasticity, and

pyrami-dal tract signs are rarely

encoun-tered (230, 869) Partial and

gener-alized seizures may occur (454)

> Ocular manifestations include

di-minished frequency of blinking

(Stellwag’s sign), lid retraction

(Graefe’s sign), and impaired

con-vergence (Möbius’s sign), as well as

uni- or bilateral exophthalmos The

latter reflects an endocrine

oph-thalmopathy, which may also cause

diplopia, ophthalmoplegia, and

op-tic neuropathy (p 661)

Diagnostic Evaluation

The diagnosis is made by the

demon-stration of an elevated serum

concen-tration of the free thyroid hormones

fT3and fT4 The TSH concentration is

low, except in the rare case of

pri-mary hypothalamic hypersecretion of

TSH

Treatment

The options for treatment include

thyrostatic drugs, thyroidectomy,

and radiotherapy The neurologic

manifestations usually resolve

once the serum thyroid hormone

concentration has been

of calcium and phosphate

homeosta-sis due to a hereditary or acquired

(often post-surgical) deficiency of

parathyroid hormone The identical

clinical picture is produced when

parathyroid hormone is present at

normal concentration, but fails to

interact normally with parathyroidhormone receptors on the surface ofthe effector cells; this is the case in

both pseudohypoparathyroidism and pseudo-pseudohypoparathyroidism.

The characteristic laboratory findingsare

> hypocalcemia,

> hypomagnesemia, and

> hyperphosphatemia

General manifestations These

dis-ease states often produce abdominalpain, nausea, and vomiting

Neurologic manifestations The

neu-rologic manifestations, largely due tohypocalcemia, include:

> Tetany is characterized by a feeling

that the extremities are “fallingasleep,” carpopedal spasm (withthe classic “obstetrician’s hand”posture), and stridor (p 554) Ob-jective findings include brisk re-flexes and positive Chvostek, Lust,and Trousseau signs

> Seizures are usually generalized

and poorly responsive to vulsants

anticon-> Headache and papilledema are seen

in hypoparathyroid states, as inpseudotumor cerebri

> Basal ganglionic dysfunction

mani-fests itself in a variety of hypo- andhyperkinetic movement disorders,e.g., choreoathetosis

> Behavioral and neurasthenic festations include abnormal fatiga-

mani-bility, apathy, confusion, tions, and psychosis

hallucina-Other manifestations Cataracts and

myopathy with an elevated creatine

kinase concentration have been

de-scribed (361) Intracranial tions, with a predilection for the basal

calcifica-ganglia, are common (p 299)

Diagnostic Evaluation

The serum concentration of

parathy-roid hormone is low in

hypoparathy-roidism The EEG changes are

nonspe-cific Hypocalcemia with a normal

parathyroid hormone concentration

is seen in chronic renal failure,

vita-min D deficiency, and (transiently) in

severe disease states of many

differ-ent kinds

Treatment

Hypoparathyroidism is treated

with vitamin D and calcium

Nor-malization of the serum calcium

and phosphate concentrations

re-sults in clinical improvement

| Hyperparathyroidism and

Hypercalcemia (609, 744, 770)

Clinical Features

Hyperparathyroidism is usually due

to a hypersecretory parathyroid

tu-mor; the classic clinical triad of

hy-perparathyroidism consists of kidney

stones (calcium oxalate or

phos-phate), ostitis fibrosa cystica, and

duodenal ulcer Its neurologic

mani-festations (see below) are caused by

hypercalcemia

Neurologic manifestations The

neu-rologic manifestations of

hyperpara-thyroidism are those of

hypercalce-mia:

> Emotional lability, fatigability,

apa-thy, agitation, insomnia,

depres-sion, nausea, vomiting, anorexia,

confusion, psychosis, progressive

lethargy, coma

> Memory impairment and

demen-tia

> Neuromuscular manifestations

with weakness and atrophy

pre-dominantly affecting the muscles

of the shoulder and pelvic girdles(958) The reflexes usually remainbrisk The EMG reveals myopathicchanges (100) Fasciculations, sen-sory deficits, paresthesiae, andhyporeflexia are occasionallyencountered

> Ataxia, oculomotor dysfunction,spasticity, dysarthria, dysphagia

demon-in the settdemon-ing of a normal or low thyroid hormone concentration in-cludes cancer (of the breast, lung,kidney, or hematopoietic system), re-nal failure, hypervitaminosis D, sar-coidosis, and diseases causing accel-erated metabolism of bone

para-Treatment

Surgical resection of a parathyroid

adenoma (if present) is curative.Hypercalcemia of other causes istreated etiologically, symptomati-cally, or both Treatment is usually

by hydration with forced diuresis and the administration of bisphos- phonates and calcitonin.

Paraneoplastic Syndromes Affecting the Nervous System

(414, 362a, 768)

Definition:

Cancer can affect the nervous system not only by primary and metastaticinvolvement and the predisposition to opportunistic infection, metabolicderangement, and ischemic and hemorrhagic stroke, but also by humorallymediated, long-distance mechanisms The specific, causative anti-neuronalantibodies have been identified for a number of these so-called paraneo-plastic syndromes

| Paraneoplastic Neurologic

Syndromes

This term designates the

long-distance effects of cancer on the

cen-tral and peripheral nervous system

that are not due to metastasis,

infec-tion, or cancer-related coagulopathy

(Table 2.86).

General Aspects

As a rule, paraneoplastic syndromes

become clinically evident before the

underlying tumor itself does, or when

the tumor is in remission, or when it is

still so small as to be curable The

syn-dromes designated as

“paraneoplas-tic” are not exclusively seen in

connec-tion with a tumor; they are seen, with

variable frequency, in nonneoplastic

autoimmune diseases, too The

likeli-hood that there is an underlying

tu-mor is so high as to merit an intensive

search for it in all cases of subacute

cerebellar degeneration,

opsoclonus-myoclonus syndrome in children, and

Lambert-Eaton myasthenic syndrome

An intensive search for a primary

tu-mor is less urgently indicated in other

paraneoplastic syndromes

Pathogenesis

An autoimmune pathogenesis is

pre-sumed for most of these syndromes

In a number of them, the responsible

autoantibody has already been tified – an antibody directed againstthe tumor, which keeps its growth incheck, but which also reacts withneurons or with an opportunistic vi-rus in the nervous system

an-detection can support the diagnosis

of particular syndromes (Table 2.87)

and can also facilitate the search for aprimary tumor In many cases of pa-raneoplastic syndrome, CSF examina-tion reveals an inflammatory picture,with pleocytosis, elevated proteinconcentration, and oligoclonal bands

to attempt treatment with immune suppressants, plasmapheresis, or in- travenous immunoglobulins (IvIG).

Plasmapheresis is generally cessful in cases of Lambert-Eatonmyasthenic syndrome, and IvIG is

suc-effective against cerebellar

degen-eration, at least when it occurs in

Paraneoplastic cerebellar atrophy is

the most common paraneoplastic

Table 2.86 Paraneoplastic syndromes of the nervous system (768)

Brain and cranial nerves:

> Subacute cerebellar degeneration

> Opsoclonus-myoclonus syndrome

> Limbic encephalitis and other dementias

> Brainstem encephalitis

> Optic neuritis

> Photoreceptor degeneration (= paraneoplastic retinopathy)

Spinal cord and spinal ganglia:

> Subacute and chronic sensorimotor polyneuropathy

> Acute polyradiculoneuropathy (Guillain-Barr´e syndrome)

> Mononeuritis multiplex, plexus neuritis

> Autonomic neuropathy

> Paraprotein-associated polyneuropathy

Neuromuscular junction and muscle:

> Lambert-Eaton myasthenic syndrome

> Stiff man syndrome

neurologic syndrome and is seenmainly in association with small-celllung cancer, ovarian cancer, andHodgkin’s lymphoma The neurologicmanifestations appear severalmonths or (rarely) years before theprimary tumor becomes symptom-atic The initial presentation is usu-ally with a mild impairment of coor-dination, which progresses within afew weeks or months to a symmetri-cal, disabling truncal and appendicu-

Table 2.87 Autoantibodies associated with paraneoplastic neurologic syndromes (207,

575, 768)

Anti-Yo = PCA-1 Cerebellar degeneration Ovarian carcinoma, breast

cancer, (rarely) lymphoma

or lung cancer

Anti-Hu = ANNA-1 Encephalomyelitis, limbic

encephalitis, myoclonus syndrome (415),sensory polyneuropathy

opsoclonus-Small-cell lung cancer, roblastoma, prostate cancer,seminoma

neu-Anti-Ri = ANNA-2 Opsoclonus-myoclonus

syn-drome Neuroblastoma, breast can-cer, small-cell lung cancer

Anti-Retina Paraneoplastic retinopathy Small-cell lung cancer

syndrome (Ab against calciumchannel)

Small-cell lung cancer

Anti-NMJ Myasthenia gravis (Ab against

acetylcholine receptor) Thymoma

Hodgkin-Ab Cerebellar degeneration Hodgkin’s lymphomaANNA: antineuronal nuclear antibody;

NMJ: neuromuscular junction;

PCA: Purkinje-cell antibody

lar ataxia with dysarthria, dysphagia,

nystagmus, oscillopsia, and vertigo

These cerebellar manifestations are

often accompanied by diplopia,

hear-ing loss, pyramidal tract signs,

poste-rior column signs, polyneuropathy, or

dementia Most patients lose the

abil-ity to walk

Diagnostic Evaluation

CT and MRI reveal cerebellar atrophy.

CSF examination usually initially

re-veals inflammatory changes, which

later resolve Antibodies that react

with Purkinje cells and other types of

neurons (some of them outside the

cerebellum) are often found in both

the serum and the CSF (Table 2.87).

Histological examination reveals a

loss of the Purkinje cells of the

cere-bellar cortex If a primary tumor is

found, it is usually still in the ized stage Anti-Yo antibodies appearonly in association with gynecologi-cal tumors; their detection shouldtherefore prompt a search for such atumor Cerebellar degeneration in as-sociation with Hodgkin’s disease ismore common in men Plasmaphere-sis or intravenous immunoglobulinscan bring clinical improvement insome cases

local-| Limbic Encephalitis (206, 954) Clinical Features

This term refers to a form of plastic encephalitis that mainly af-fects the structures of the limbic sys-tem and is most commonly seen inassociation with small-cell lung can-cer, though it may also accompany

paraneo-tumors of other kinds Over the

course of a few weeks, patients

de-velop a severe deficit of explicit

memory, along with personality

changes, affective disturbances,

con-fusion, and sometimes agitation,

hal-lucinations, and both partial and

gen-eralized seizures

Diagnostic Evaluation

The CSF initially displays

inflamma-tory changes, and MRI reveals signal

abnormalities in the medial portions

of the temporal lobes Histological

ex-amination reveals neuronal loss,

re-active gliosis, and perivascular

lym-phocytic infiltration predominantly

affecting the limbic and insular

cor-tex

Treatment

There is no known effective

treat-ment The syndrome sometimes

improves with treatment of the

primary tumor

| Other Paraneoplastic

Syndromes

There are paraneoplastic syndromes

affecting many different parts of the

nervous system, e.g., paraneoplastic

brainstem encephalitis, autonomic

neuropathy, and myelitis (206, 574).

Further syndromes are listed in

Ta-ble 2.87.

The antibody Anti-Hu is associated

with a number of paraneoplastic

syn-dromes; the one originally described

under the name “Anti-Hu syndrome”

is a sensory polyneuropathy

associ-ated with small-cell lung cancer (206,

358) Anti-Ri is histochemically

iden-tical with Anti-Hu, but reacts only

with central neurons; it causes

oculo-motor disturbances and, less

fre-quently, cerebellar dysfunction (207)

| Ischemic and Hemorrhagic

Stroke Associated with Neoplasia (74)

Stroke occurs in 15% of cases of cer (about equally divided betweenischemic and hemorrhagic stroke)and is thus the second most frequentcancer-associated disturbance affect-ing the CNS (after metastases) Somespecial features of cancer-associatedstroke are the following:

can-> The presentation may be with adiffuse encephalopathic syndromerather than with an acute focal def-icit

> Stroke may be more likely to be of aparticular type (ischemic or hem-orrhagic) in the setting of certainprimary tumors, patterns of CNSinvolvement, and modes of anti-tumor therapy

> Most strokes in cancer patientshave the same etiology and patho-genesis as in persons not sufferingfrom cancer

> The following causes of stroke are

of particular relevance in cancerpatients:

– coagulopathy (disseminated travascular coagulation, protein

in-C deficiency, thrombocytosis)– nonbacterial thrombotic endo-carditis

– vasculitis– paraneoplastic syndrome– compression or erosion of ablood vessel by tumor

– leptomeningeal metastasis– neoplastic angioendotheliosis– tumor embolus (mucin, frag-ment)

– infection, sepsis– adverse effect of treatment (ra-diation, chemotherapy, surgery)– atherosclerosis

– thrombotic microangiopathy

Stroke in cancer patients is usually

treated as in other patients

Patients with nonbacterial

throm-botic endocarditis, and probably

also those with disseminated

intra-vascular coagulation, need

second-ary prophylaxis with heparin, cause vitamin K antagonists are in-effective in this situation Vasculitis

be-can be treated with corticosteroids and cyclophosphamide, while plas- mapheresis is beneficial in throm-

usu-Connective tissue diseases and

auto-immune diseases affect the nervous

system in many different ways

Head-ache and atypical complaints are

common in the early phase, before

neurologic deficits appear or the

dis-ease declares itself through the more

usual manifestations affecting the

skin, joints, muscles, kidneys, and

other organs Common

manifesta-tions in the central nervous system

include stroke, seizures, and

neuro-psychological deficits; in the

periph-eral nervous system,

mononeuropa-thy multiplex, isolated

mononeurop-athy, symmetric polyneuropmononeurop-athy, and

myositis

A list of vasculitides affecting the

ner-vous system is found in Table 2.49, p.

197 Vasculitis is rarely confined to a

single organ The central or

periph-eral nervous system may be the site

at which the disorder first appears,

but even then systemic

manifesta-tions are usually evident, such as ver, malaise, or weight loss Theerythrocyte sedimentation rate (ESR)and serum concentration of C-reactive protein (CRP) are usually ele-vated, and the peripheral bloodsmear has an inflammatory pattern.Serologic tests and tissue biopsiesmay aid in establishing the diagnosis.For further discussion of the myositi-des, see p 908

fe-| Polyarteritis Nodosa (PAN) and

Related Diseases (200, 673)

This disease, also called periarteritisnodosa, produces a granulocytic andeosinophilic infiltrate in the arterialwall, with resulting necrosis of thetunica media Aneurysms that form atthe sites of necrosis become thick-ened by fibrosis PAN affects multipleorgan systems, primarily the kidneys,heart, liver, and gastrointestinal tract

Cogan’s syndrome This disorder,

which primarily affects the cranial

nerves, may be a variant of PAN (p

703) (46, 983)

Churg-Strauss syndrome.

Churg-Strauss syndrome is another form of

allergic granulomatous angiitis

re-lated to PAN It affects not only the

ar-teries, but also the veins and venules

Its principal manifestations are

se-vere asthma and marked

eosino-philia It more commonly affects the

peripheral than the central nervous

system; painful mono- or

polyneu-ropathy is typical (919)

Severe atherosclerosis In severe

ath-erosclerosis, breakdown of an

athero-matous plaque may result in

emboli-zation of plaque material, containing

cholesterol crystals, into all organs of

the body, including the brain The

characteristic appearance of ischemia

in the toes has given rise to the name

“purple (or blue) toe syndrome.”

Em-bolization is followed by

inflamma-tory changes in the affected vessels

that may be mistaken for a primary

vasculitis or PAN (189)

Buerger’s disease (thrombangiitis

ob-literans) This disorder affects young

male smokers (723e) and involves

in-flammatory changes in the small and

mid-sized arteries and veins, as well

as in the vasa nervorum Its principal

manifestations are intermittent

clau-dication, pain in the legs at rest,

is-chemic ulcers, thrombophlebitis,

Raynaud’s syndrome, and sensory

deficits (more commonly in the legs

than in the arms) Serologic tests are

negative

Clinical Features

PAN begins with nonspecific toms and signs such as fever, tachy-cardia, diaphoresis, weight loss, fa-tigue, generalized weakness, myalgia,and abdominal complaints Organ-specific manifestations may, however,

symp-be present at the onset of disease.Mono- or polyneuropathy affects half

of all patients (p 606), while centralnervous manifestations occur in one-quarter The latter produce:

prednisone (1 mg/kg qd) and phosphamide (2 mg/kg p.o qd with

cyclo-a tcyclo-arget white blood count of 3000/

‘ L, or 1 g/m2as a monthly bolus).The treatment must be continuedfor at least 6 months, and usually

longer Mesna should be given

con-comitantly to prevent city

nephrotoxi-Patients in remission must be

fol-lowed up regularly Azathioprine

(1–2 mg/kg p.o qd) can be given toprevent recurrences If recurrencenonetheless occurs, restartingprednisone and cyclophosphamidegenerally results in remission

| Isolated CNS Angiitis

(23, 383, 674)

This disorder, also known as isolated

CNS vasculitis and as granulomatous

angiitis of the central nervous system

(GANS), affects only the CNS – usually

only the brain, sometimes also the

spinal cord Some authors classify it

among the giant cell arteritides (the

other members of this group are

cra-nial arteritis, polymyalgia

rheuma-tica, and Takayasu’s arteritis)

Clinical Features

The major manifestations are

head-ache and multifocal cerebral ischemia

or encephalopathy without focal

neu-rologic signs

Diagnostic Evaluation

The CSF may display inflammatory

changes Angiography usually (though

not always) reveals vasculitic

changes, with stenoses, dilatations,

occlusions, and collateral flow MRI

reveals multiple foci of ischemia or

hemorrhage in the basal ganglia,

cor-tex, and subcortical white matter

(359) Leptomeningeal and cortical

biopsy are required for definitive

di-agnosis

Differential Diagnosis

The major differential diagnoses of

isolated CNS angiitis are vasculitides

in the setting of herpes zoster,

lym-phoma, sarcoidosis, and the entire

spectrum of chronic meningitis

Treatment

Isolated CNS angiitis has an

unfa-vorable prognosis if untreated

Prednisone and cyclophosphamide

are beneficial (for doses, see under

PAN, above)

| Takayasu’s Arteritis

This inflammatory disease of theaorta and its branches produces fever,night sweats, and weight loss, as well

as neurologic manifestations: ache, orthostatic lightheadedness,transient ischemic attacks, andstroke Blurred vision on standing up

sys-tract and the kidneys Its common

neurologic manifestations are: