The Gale Encyclopedia of Neurological Disorders vol 2 - part 2 ppsx

Huntington’s disease A rare hereditary condition that causes progressive chorea jerky muscle move-ments and mental deterioration that ends in de-mentia.. Richard Robinson Definition Moya

Key TermsBotulinum toxin Any of a group of potent bacterial

toxins or poisons produced by different strains of the

bacterium Clostridium botulinum The toxins cause

muscle paralysis, and thus force the relaxation of a

muscle in spasm

Cerebral palsy A movement disorder caused by a

permanent brain defect or injury present at birth or

shortly after It is frequently associated with

prema-ture birth Cerebral palsy is not progressive

Computed tomography (CT) An imaging technique

in which cross-sectional x rays of the body are

com-piled to create a three-dimensional image of the

body’s internal structures

Encephalopathy An abnormality in the structure or

function of tissues of the brain

Essential tremor An uncontrollable (involuntary)

shaking of the hands, head, and face Also called

fa-milial tremor because it is sometimes inherited, it

can begin in the teens or in middle age The exact

cause is not known

Fetal tissue transplantation A method of treating

Parkinson’s and other neurological diseases by

graft-ing brain cells from human fetuses onto the basal

ganglia Human adults cannot grow new brain cells

but developing fetuses can Grafting fetal tissue

stim-ulates the growth of new brain cells in affected adult

brains

Hereditary ataxia One of a group of hereditary

de-generative diseases of the spinal cord or cerebellum

These diseases cause tremor, spasm, and wasting of

muscle

Huntington’s disease A rare hereditary condition

that causes progressive chorea (jerky muscle

move-ments) and mental deterioration that ends in

de-mentia Huntington’s symptoms usually appear in

patients in their 40s There is no effective treatment

Levodopa (L-dopa) A substance used in the

treat-ment of Parkinson’s disease Levodopa can cross the

blood-brain barrier that protects the brain Once in

the brain, it is converted to dopamine and thus can

replace the dopamine lost in Parkinson’s disease

Magnetic resonance imaging (MRI) An imaging

technique that uses a large circular magnet and radiowaves to generate signals from atoms in the body.These signals are used to construct images of internalstructures

Parkinson’s disease A slowly progressive disease

that destroys nerve cells in the basal ganglia and thuscauses loss of dopamine, a chemical that aids intransmission of nerve signals (neurotransmitter).Parkinson’s is characterized by shaking in restingmuscles, a stooping posture, slurred speech, muscu-lar stiffness, and weakness

Positron emission tomography (PET) A diagnostic

technique in which computer-assisted x rays are used

to track a radioactive substance inside a patient’sbody PET can be used to study the biochemical ac-tivity of the brain

Progressive supranuclear palsy A rare disease that

gradually destroys nerve cells in the parts of the brainthat control eye movements, breathing, and musclecoordination The loss of nerve cells causes palsy, orparalysis, that slowly gets worse as the disease pro-gresses The palsy affects ability to move the eyes,relax the muscles, and control balance

Restless legs syndrome A condition that causes an

annoying feeling of tiredness, uneasiness, and itchingdeep within the muscle of the leg It is accompanied

by twitching and sometimes pain The only relief is inwalking or moving the legs

Tourette syndrome An abnormal condition that

causes uncontrollable facial grimaces and tics andarm and shoulder movements Tourette syndrome isperhaps best known for uncontrollable vocal tics thatinclude grunts, shouts, and use of obscene language(coprolalia)

Wilson’s disease An inborn defect of copper

me-tabolism in which free copper may be deposited in avariety of areas of the body Deposits in the brain cancause tremor and other symptoms of Parkinson’sdisease

progress, “sculpting” the barrage of voluntary commands

into a tightly controlled, constantly evolving pattern

Cere-bellar disorders cause inability to control the force, fine

positioning, and speed of movements (ataxia) Disorders

of the cerebellum may also impair the ability to judge tance so that a person under- or overreaches the target(dysmetria) Tremor during voluntary movements can alsoresult from cerebellar damage

within the brain that help control involuntary components

of movement (basal ganglia) The basal ganglia send

out-put messages to the motor cortex, helping to initiate

move-ments, regulate repetitive or patterned movemove-ments, and

control muscle tone

Circuits within the basal ganglia are complex Withinthis structure, some groups of cells begin the action of

other basal ganglia components and some groups of cells

block the action These complicated feedback circuits are

not entirely understood Disruptions of these circuits are

known to cause several distinct movement disorders A

portion of the basal ganglia called the substantia nigra

sends electrical signals that block output from another

structure called the subthalamic nucleus The subthalamic

nucleus sends signals to the globus pallidus, which in turn

blocks the thalamic nuclei Finally, the thalamic nuclei

send signals to the motor cortex The substantia nigra,

then, begins movement and the globus pallidus blocks it

This complicated circuit can be disrupted at severalpoints For instance, loss of substantia nigra cells, as in

Parkinson’s disease, increases blocking of the thalamic

nu-clei, preventing them from sending signals to the motor

cortex The result is a loss of movement (motor activity),

other movement disorders, although the exact mechanisms

are not well understood

Some movement disorders, including Huntington’sdisease and inherited ataxias, are caused by inherited ge-

netic defects Some diseases that cause sustained muscle

contraction limited to a particular muscle group (focal

dys-tonia) are inherited, but others are caused by trauma The

cause of most cases of Parkinson’s disease is unknown,

al-though genes have been found for some familial forms

Symptoms

Abnormal movements are broadly classified as eitherhyperkinetic—too much movement—and hypokinetic—

too little movement Hyperkinetic movements include:

• Dystonia: sustained muscle contractions, often causing

twisting or repetitive movements and abnormal postures

Dystonia may be limited to one area (focal) or may affectthe whole body (general) Focal dystonias may affect theneck (cervical dystonia or torticollis), the face (one-sided

or hemifacial spasm, contraction of the eyelid or pharospasm, contraction of the mouth and jaw or oro-

ble-mandibular dystonia, simultaneous spasm of the chin andeyelid or Meige syndrome), the vocal cords (laryngealdystonia), or the arms and legs (writer’s cramp, occupa-tional cramps) Dystonia may be painful as well as inca-pacitating

• Tremor: uncontrollable (involuntary) shaking of a bodypart Tremor may occur only when muscles are relaxed

or it may occur only during an action or holding an tive posture

ac-• Tics: involuntary, rapid, nonrhythmic movement orsound Tics can be controlled briefly

•Myoclonus: a sudden, shock-like muscle contraction.

Myoclonic jerks may occur singly or repetitively Unliketics, myoclonus cannot be controlled even briefly

•Chorea: rapid, nonrhythmic, usually jerky movements,

most often in the arms and legs

• Ballism: like chorea, but the movements are much larger,more explosive and involve more of the arm or leg Thiscondition, also called ballismus, can occur on both sides

of the body or on one side only (hemiballismus)

• Akathisia: restlessness and a desire to move to relieveuncomfortable sensations Sensations may include a feel-ing of crawling, itching, stretching, or creeping, usually

in the legs

• Athetosis slow, writhing, continuous, uncontrollablemovement of the arms and legs

Hypokinetic movements include:

• Bradykinesia: slowness of movement

• Freezing: inability to begin a movement or involuntarystopping of a movement before it is completed

• Rigidity: an increase in muscle tension when an arm orleg is moved by an outside force

• Postural instability: loss of ability to maintain uprightposture caused by slow or absent righting reflexes

Diagnosis

Diagnosis of movement disorders requires a carefulmedical history and a thorough physical and neurologicalexamination Brain imaging studies are usually performed.Imaging techniques include computed tomography scan(CT scan), positron emission tomography (PET), or magnetic resonance imaging (MRI) scans Routine

blood and urine analyses are performed A lumbar ture (spinal tap) may be necessary Video recording of theabnormal movement is often used to analyze movementpatterns and to track progress of the disorder and its treat-ment Genetic testing is available for some forms of move-ment disorders

deter-help make up for lost control and strength Drug therapy

can help compensate for some imbalances of the basal

ganglionic circuit For instance, levodopa (L-dopa) or

re-lated compounds can substitute for lost

dopamine-pro-ducing cells in Parkinson’s disease Conversely, blocking

normal dopamine action is a possible treatment in some

hyperkinetic disorders, including tics Oral medications

can also help reduce overall muscle tone Local injections

of botulinum toxin can selectively weaken overactive

muscles in dystonia and spasticity Destruction of

periph-eral nerves through injection of phenol can reduce

spas-ticity All of these treatments may have some side effects

Surgical destruction or inactivation of basal glionic circuits has proven effective for Parkinson’s dis-

gan-ease and is being tested for other movement disorders

Transplantation of fetal cells into the basal ganglia has

produced mixed results in Parkinson’s disease

There are several alternative therapies that can be ful when treating movement disorders The progress made

use-will depend on the individual and his/her condition

Among the therapies that may be helpful are

acupunc-ture, homeopathy, touch therapies, postural alignment

therapies, and biofeedback

Martini, Frederic Fundamentals of Anatomy and Physiology.

Englewood Cliffs, NJ: Prentice Hall, 1989.

Watts, Ray L., and William C Koller, eds Movement

Disorders: Neurologic Principles and Practice New

York: McGraw-Hill, 1997.

ORGANIZATIONS

Worldwide Education and Awareness for Movement Disorders.

One Gustave L Levy Place, Box 1052, New York, NY

10029 (800) 437-6683 <http://www.wemove.org>.

Richard Robinson

Definition

Moyamoya disease is a rare disorder of blood vessels

in the brain known as internal carotid arteries (ICA) The

condition is characterized by stenosis (narrowing) or

oc-clusion (blockage) of one or both ICA with subsequent

formation of an abnormal network of blood vessels cent to the ICA

adja-Description

Moyamoya disease was first described in Japan in

1955 The term moyamoya, a Japanese word that means

“puff of smoke,” describes the appearance of the abnormalvessels that form adjacent to the internal carotid arteries.Alternate names for the disorder include spontaneous oc-clusion of the circle of Willis, and basal occlusive diseasewith telangiectasia

Moyamoya disease can occur in children (juveniletype) or in adults (adult type) Children tend to be less thanage 10 and adults are usually between ages 30 and 49 Af-fected individuals typically present with signs of stroke or

other types of cerebral ischemia (decreased blood flow to

an area of the brain due to obstruction in an artery), bral hemorrhage (bleeding), or seizures (mainly in chil-

cere-dren) Symptoms in an affected child or adult may includedisturbed consciousness, speech deficits, sensory and cog-nitive impairment, involuntary movements, or vision prob-lems Options for treatment for people with moyamoyadisease consist of medications and brain surgery Withouttreatment, repeated strokes, transient ischemic attacks,brain hemorrhages, or seizures can lead to serious cogni-tive impairment, physical disability, or death

Demographics

Moyamoya disease occurs worldwide and is mostprevalent in Asia, and especially in Japan According to areport in 1998, more than 6000 cases had been described.The disease occurs in about one in a million people peryear Estimates of disease incidence in Japan are as much

as ten times greater Slightly more females than males areaffected The male-to-female ratio has been reported to bearound 2:3 Approximately 10% of cases of moyamoyadisease are familial

Causes and symptoms

The cause of moyamoya disease is unknown Possibleexplanations for the disorder include injuries to the brain,infection, multifactorial inheritance, genetic factors, orother causes For example, moyamoya disease has beenassociated with meningitis,radiation therapy to the skull

in children, and genetic conditions such as Down drome,neurofibromatosis, and sickle cell anemia Also,

syn-there have been reports linking a region on chromosome 3(named MYM1) and a region on chromosome 17 (namedMYM2) to moyamoya disease in some families

The initial symptoms of moyamoya disease are what different in children and adults In children, there isischemia due to stenosis and occlusion of the circle of

brain with consequent brain damage A stroke may

be caused by a blood clot or by hemorrhage due to

a burst blood vessel Also known as a cular accident

cerebrovas-Transient ischemic attacks A brief interruption of

the blood supply to part of the brain that causes atemporary impairment of vision, speech, or move-ment Usually, the episode lasts for just a few mo-ments, but it may be a warning sign for a full-scalestroke

Willis, a ring of arteries at the base of the brain In

chil-dren, the disease tends to cause repeated “mini-strokes”

known as transient ischemic attacks (TIAs) or, less often,

seizures The TIAs usually manifest as weakness of one

side of the body (hemiparesis), speech disturbances, and

sensory deficits TIAs may be made worse by

hyperventi-lation, such as with intense crying Involuntary movements

may occur Mental retardation may be present.

Adults with moyamoya disease typically present withbleeding in the brain (cerebral hemorrhage) or strokes

Cerebral hemorrhage occurs as a result of breakdown of

the coexisting blood vessels that formed earlier in life due

to stenosis or occlusion of the ICA The cerebral

hemor-rhages are commonly located in the thalamus, basal

gan-glia, or deep white matter of the brain Symptoms can

include disturbance of consciousness and/or hemiparesis

Adult patients with moyamoya disease may go on to have

further hemorrhages and strokes which can result in

sig-nificant and irreversible brain damage

Diagnosis

A diagnosis of moyamoya disease is based on ings from neuroradiologic studies and on clinical signs

find-consistent with this diagnosis Neuroradiologic studies

used to establish the diagnosis of moyamoya disease

in-clude cerebral angiography, magnetic resonance

im-aging (MRI), magnetic resonance angiography (MRA),

and computed tomography (CT) scan Cerebral

angiogra-phy is the most common means of confirming a diagnosis

of moyamoya disease There are reports indicating that

MRI and MRA, which are less invasive procedures, may

be used instead of cerebral angiography CT scan findings

tend to be non-specific and not as useful as CA, MRI, and

MRA in making the diagnosis

Characteristic brain findings in moyamoya diseaseinclude narrowing or occlusion of the end portion of one

or both internal carotid arteries, an abnormal network

or blood vessels at the base of the brain, and presence ofthese findings on both sides of the brain In about 10%

of cases, cerebralaneurysms may also be found Nuclear

medicine studies such as Xenon-enhanced CT, tron emission tomography (PET), or single photon

posi-emission computed tomography (SPECT) may be formed in order to evaluate cerebral blood flow (CBF)patterns The information obtained from CBF studieshelps the neurologist and/or neurosurgeon to devise a

per-treatment plan

Treatment

There is no cure for moyamoya disease Early ment is important to avoid mental and physical impair-ment Treatment options include medications and surgicalrevascularization

treat-Medications Individuals having TIAs and stroke may

be given antiplatelet drugs, vasodilators, or anticoagulants

to help prevent future attacks Steroid therapy may beprescribed for a person who has involuntary movements.For a patient with a cerebral hemorrhage, treatment mayinclude management of hypertension, if present

Surgery The purpose of revascularization surgery inmoyamoya disease is to augment or redirect blood flow inthe brain Surgical revascularization has been reported toimprove cerebral blood flow, to reduce ischemic attacks,and, in children, to increase IQ The optimal method ofsurgery depends on the patient’s history and clinical status.There are various direct and indirect methods of restoringblood supply in the brain Examples of direct bypass sur-gery include techniques known as superficial temporalartery to middle cerebral artery bypass, and extracranial-intracranial bypass to anterior or posterior cerebral artery.Examples of indirect bypass surgery include techniquesknown as encephaloduroarteriosynangiosis, encephalo-myosynangiosis, and encephaloarteriosynangiosis

Treatment team

Management of moyamoya disease requires a disciplinary approach In addition to the patient’s primaryhealth care professionals, medical professionals involved

multi-in the care of patients with moyamoya disease generallyinclude specialists in neurology, neurosurgery, neuroradi-ology, and anesthesiology Specialists in orthopedic sur-gery, ophthalmology, rehabilitation, physical therapy,occupational therapy, speech therapy, and mental healthmay also be involved in the care of affected individuals.Psychological counseling and contact with other affected

patients may assist families in coping with this condition,

especially given it’s rarity

Recovery and rehabilitation

The potential for rehabilitation in moyamoya diseasedepends in part on the degree of impairment caused by

complications such as strokes, cerebral hemorrhages, and

seizures Interventions such as physical, occupational, and

speech therapy may be recommended for management of

problems such as hemiparesis, speech problems, and

sen-sory deficits Some patients may require assistance with

daily living In cases in which there is significant

disabil-ity, consideration may be given to in-home nursing care or

placement in a residential care facility that can provide

24-hour care and support services

Clinical trials

As of 2004, there were noclinical trials specifically

for patients with moyamoya disease As more is learned

about the causes of moyamoya disease, it is hoped that

novel therapies may be developed in the future As of 2004,

one laboratory listed on the GeneTests web site (www

genetests.org) was conducting genetic research on

moya-moya disease Interested patients may discuss the

feasibil-ity of participating in this research with their physician

Prognosis

As of 2004, the prognosis for moyamoya disease wasnot well defined The prognosis depends in part on the ex-

tent of brain injury present at the time of diagnosis and the

success of treatment For example, a person who had a

major stroke or cerebral hemorrhage may already be

per-manently impaired, both physically and mentally Reports

of clinical outcome after treatment are mixed Some

indi-viduals experience improvement of symptoms while

oth-ers continue to show progressive decline Moyamoya

disease tends to be more progressive in children than in

adults In those patients who don’t stabilize clinically,

sig-nificant disability or death may occur

Special concerns

Children with moyamoya disease may have learningdisabilities or mental retardation They may also experi-

ence physical disabilities that impact academic

perform-ance Such children may be eligible to have an Individual

Education Plan (IEP) An IEP provides a framework from

which administrators, teachers, and parents can meet the

educational needs of a child with special learning needs

Depending upon severity of symptoms and the degree of

learning difficulties, some children with moyamoya

dis-ease may be best served by special education classes or a

private educational setting

Resources BOOKS

Ikezaki, Kiyonobu and Christopher M Loftus, eds Moyamoya

Disease Rolling Meadows, IL: American Association of

Neurological Surgeons, 2001.

Parker, James N., and Philip M Parker, eds The Official

Parent’s Sourcebook on Moyamoya Disease: A Revised and Updated Directory for the Internet Age San Diego,

CA: ICON Health Publications, 2002.

PERIODICALS

Ikezaki, K “Rational approach to treatment of moyamoya

dis-ease in childhood.” Journal of Child Neurology 15

(November 2000): 350–6.

Kobayashi, E., N Saeki, H Oishi, S Hirai, and A Yamaura.

“Long-term natural history of hemorrhagic moyamoya

disease in 42 patients.” Journal of Neurosurgery 93

(December 2000): 976–80.

Lamphere, K “Moyamoya disease An uncommon cause of

stroke in the young.” Adv Nurse Pract 11 (2003): 63–6.

Shetty-Alva, N., and S Alva “Familial moyamoya disease in

Caucasians.” Pediatric Neurology 23 (November 2000):

445–7.

Yonekawa, Y., and N Kahn “Moyamoya disese.” Advances in

Neurology 92 (2003): 113–118.

WEBSITES

The National Institute of Neurological Disorders and Stroke

(NINDS) Moyamoya Disease Information Page.

14 15 16

13 12 11 11 12 13

2

1

HD: Huntington disease

MPS: Mucopolysaccharidoses Achondroplasia

RIEG: Rieger syndrome

p q

25

27

31

33 34 35 32 28

24

26

23 22 21

3

1

LQT4: Long QT syndrome 4 alpha-synuclein: Parkinson’s disease

Chromosome 4

EVC: Ellis-van Creveld

Mucopolysaccharidoses, on chromosome 4 (Gale Group.)

Description

Though the symptoms and severity vary for eachMPS disorder, common features include enlarged organs

(organomegaly), dysostosis multiplex (abnormal bone

for-mation), and a characteristic facial appearance Hearing,

vision, breathing, heart function, joint mobility, and

men-tal capacity may also be affected As of 2003, seven types

of MPS have been classified The MPS disorders are

caused by absent or insufficient production of proteins

known as lysosomal enzymes The specific enzyme that is

deficient or absent distinguishes one type of MPS from

an-other However, before these enzymes were identified, the

signs and symptoms expressed by an affected individual

led to the diagnosis The discovery of these enzymes

re-sulted in a reclassification of some of the MPS disorders

These conditions are often referred to as MPS I, MPS II,

MPS III, MPS IV, MPS VI, MPS VII, and MPS IX and

may also referred to by their original names, which are

Hurler (MPS I H), Hurler-Scheie (MPS I H/S), Scheie

(MPS I S), Hunter (MPS II), Sanfilippo (MPS III),

Morquio (MPS IV), Maroteaux-Lamy (MPS VI), Sly

(MPS VII), and Hyaluronidase deficiency (MPS IX)

Demographics

The MPS syndromes are considered to be rare filippo syndrome appears to be the most common MPS

San-with a reported incidence of one in 70,000 The incidence

of Hyaluronidase deficiency is not yet known The

inci-dence of the remaining six classes of MPS are estimated

to be: one in 100,000 for Hurler syndrome; one in 500,000

for Scheie syndrome; one in 115,000 for Hurler/Scheie

disease; one in 100,000 (male live births) for Hunter

syn-drome (mild and severe combined); one in 100,000 to one

in 300,000 for Morquio syndrome (types A and B

in-cluded); one in 215,000 for Maroteaux-Lamy syndrome;

and less than one in 250,000 for Sly syndrome These

fig-ures are general; more exact figfig-ures have been reported for

individual MPS disorders in certain countries

Causes and symptoms

All of the MPS are genetic conditions MPS I, MPSIII, MPS IV, MPS VI, MPS VII, and MPS IX are inherited

in an autosomal recessive manner which means that

af-fected individuals have two altered or non-functioning

genes, one from each parent, for a specific enzyme that is

needed to break down mucopolysaccharides MPS II

(Hunter syndrome) is inherited in an X-linked manner

which means that the gene for MPS II is located on the X

chromosome, one of the two sex chromosomes Hunter

syndrome primarily affects males because they have only

one X chromosome and therefore lack a second, normal

copy of the gene responsible for the condition Carriers for

the autosomal recessive forms of MPS have one normalcopy and one non-working copy of the MPS gene in ques-tion Female carriers of the X-linked MPS (MPS II) haveone X chromosome with a normal gene for the condition(the IDS gene) and one X chromosome with a non-work-ing IDS gene

The enzymes that are deficient in the MPS disordersnormally break down a type of mucopolysaccharide (along chain of sugar molecules) in the body known as gly-cosaminoglycans (GAGs) Glycosaminoglycans are es-sential for building the bones, cartilage, skin, tendons, andother tissues in the body Normally, the human body con-tinuously breaks down and builds GAGs There are severalenzymes involved in breaking down each GAG and a de-ficiency or absence of any of the essential enzymes cancause one or more GAGs to accumulate in the tissues andorgans in the body When too much GAG is stored, organsand tissues can be damaged or not function properly The

accumulating material is stored in cellular structures called

lysosomes, and these disorders are also known as

lysoso-mal storage diseases

MPS I

Mutations in the alpha-L-iduronidase (IDUA) genelocated on chromosome 4 cause the MPS I disorders

(Hurler, Hurler-Scheie, and Scheie syndromes) Initially,

these three disorders were believed to be separate because

each was associated with different physical symptoms and

prognoses However, once the underlying cause of these

conditions was identified, it was recognized that all three

were variants of the same disorder

MPS I H (HURLER SYNDROME) Individuals withHurler syndrome tend to have the most severe form of

MPS I Hurler syndrome may also be referred to as severe

MPS I Infants with Hurler syndrome appear normal at

birth and typically begin to develop normally Symptoms

of Hurler syndrome are often evident within the first year

or two after birth Many of these infants may initially grow

faster than expected, but their growth slows and typically

stops by age three Facial features also begin to appear

coarse; affected children develop a short nose, flatter face,

thicker skin, and a protruding tongue Additionally, their

heads become larger and they develop more hair on their

bodies with the hair becoming coarser Affected children

with Hurler syndrome lose previously attained skills

(milestones) and eventually suffer from profound mental

retardation Progressive abnormal development of all

bones of the body (dysostosis multiplex) occurs in all

chil-dren with Hurler syndrome Chilchil-dren usually develop joint

contractures (stiff joints), kyphosis (a “hunchback” curve

of the spine), and broad hands with short fingers Many of

these children experience breathing difficulties, and

res-piratory infections are common Other common problems

include heart valve dysfunction, cardiomyopathy

(weak-ness of the heart muscle), hepatosplenomegaly (enlarged

spleen and liver), clouding of the cornea, hearing loss, and

carpal tunnel syndrome Children with Hurler syndrome

typically die within the first ten years of life

MPS I H/S (HURLER-SCHEIE SYNDROME) Scheie syndrome is felt to be the intermediate form of MPS

Hurler-I, meaning that the symptoms are not as severe as those in

individuals who have Hurler syndrome but not as mild as

those with Scheie syndrome Hurler-Scheie syndrome may

also be referred to as intermediate MPS I Individuals with

Hurler-Scheie syndrome tend to be shorter than expected

and may develop some of the physical features seen in

Hurler syndrome, but usually they are not as severe

Intel-lectual ability varies; individuals have normal or near

nor-mal intelligence The prognosis for children with

Hurler-Scheie syndrome is variable with some individuals

dying during childhood and others living to adulthood

MPS I S (SCHEIE SYNDROME) Scheie syndrome is sidered the mild form of MPS I Individuals with Scheiesyndrome usually have normal intelligence, but there havebeen some reports of affected individuals developing psy-chiatric problems Common physical problems includecorneal clouding, heart abnormalities, and orthopedic dif-ficulties involving the hands and back Individuals withScheie syndrome do not develop the facial features seenwith severe MPS I Usually life span is normal

con-MPS II (Hunter syndrome)

Mutations in the iduronate-2-sulphatase (IDS) genecause both forms of MPS II (mild and severe) Nearly allindividuals with Hunter syndrome are male, because thegene that causes the condition is located on the X chro-mosome The severe form is associated with progressivemental retardation and physical disability, with most indi-viduals dying before age 15 Males with the mild form ofHunter syndrome usually have have normal or near normalintelligence They tend to develop physical differencessimilar to males with the severe form, but not as quickly.Most males with Hunter syndrome develop joint stiffness,chronic diarrhea, enlarged liver and spleen, heart valveproblems, hearing loss, kyphosis, and tend to be shorterthan expected Men with mild Hunter syndrome can have

a normal life span and some have had children

MPS III (Sanfilippo syndrome)

MPS III is a variable condition with symptoms ginning to appear between ages two and six years of age.The condition is characterized by developmental delay, be-havioral problems, and mild physical problems (as com-pared to other types of MPS) Specific problems include:

be-seizures, sleeplessness, thick skin, joint contractures,

en-larged tongues, cardiomyopathy, hyperactivity, and tal retardation The life expectancy in MPS III is alsovariable On average, individuals with MPS III live untiladolescence Initially, the diagnosis of MPS III, like theother MPS conditions, was clinical; the diagnosis wasmade by observation of certain physical characteristics Itwas later discovered that a deficiency in one of four en-zymes could lead to the developmental delay and physicalsymptoms associated with MPS III Each type of MPS III

men-is now subdivided into four groups, labeled A-D, ing to the specific enzyme deficiency All four of these en-zymes help to break down the same GAG, heparan sulfate

accord-MPS IIIA (SANFILIPPO SYNDROME TYPE A) MPS IIIA

is caused by a deficiency of the enzyme heparan sulfatesulfamidase, due to mutations in the SGSH gene on chro-mosome 17 Type IIIA is felt to be the most severe of thefour types, in which symptoms appear and death occurs at

an earlier age

Key TermsCarpal tunnel syndrome A condition caused by

compression of the median nerve in the carpal nel of the hand, characterized by pain

tun-Cornea The clear, dome-shaped outer covering of

the eye that lies in front of the iris and pupil Thecornea lets light into the eye

Gene A building block of inheritance, which

contains the instructions for the production of aparticular protein, and is made up of a molecularsequence found on a section of DNA Each gene isfound on a precise location on a chromosome

Hydrops fetalis A condition in which a fetus or

newborn baby accumulates fluids, causing swollenarms and legs and impaired breathing

Metabolic Refers to the chemical reactions in

liv-ing organisms

Mucopolysaccharide A complex molecule made

of smaller sugar molecules strung together to form

a chain It is found in mucous secretions and cellular spaces

inter-Mutation A permanent change in the genetic

ma-terial that may alter a trait or characteristic of an dividual, or manifest as disease This change can betransmitted to offspring

in-MPS IIIB (SANFILIPPO SYNDROME TYPE B) MPS IIIB

is due to a deficiency in

N-acetyl-alpha-D-glu-cosaminidase due to mutations in the NAGLU gene, also

located on chromosome 17 This type of MPS III is not felt

to be as severe as Type IIIA and the characteristics vary

Type IIIB is the most common of the four types of MPS III

in southeastern Europe

MPS IIIC (SANFILIPPO SYNDROME TYPE C) A ciency in the enzyme acetyl-CoA-alpha-glucosaminide

defi-acetyltransferase causes MPS IIIC This is considered a

rare form of MPS III The gene involved in MPS IIIC is

believed to be located on chromosome 14

MPS IIID (SANFILIPPO SYNDROME TYPE D)MPS IIID

is caused by a deficiency in the enzyme

N-acetylglu-cosamine-6-sulfatase, due to mutations in the GNS gene

lo-cated on chromosome 12 This form of MPS III is also rare

MPS IV (Morquio syndrome)

Morquio syndrome is characterized by severe tal deformities and their secondary effects on the nervous

skele-system Intelligence is usually normal One of the earliest

symptoms seen in this condition is a difference in the way

the child walks Skeletal abnormalities can be extreme andinclude dwarfism, kyphosis (outward-curved spine),prominent breastbone, flat feet, and genu-valgum (knock-knees) A bone deformity known as odontoid hypoplasia(improper formation of the bones that stabilize the headand neck) can result in compression of the spinal cord, apotentially serious and life-threatening complication Aswith several of the MPS disorders, Morquio syndrome wasoriginally diagnosed by the presence of particular signsand symptoms However, it is now known that the defi-ciency of two different enzymes can result in MPS IV.These two types of MPS IV are called MPS IV A and MPS

IV B MPS IV is variable in its severity MPS IV A is theclassic (typical) or the severe form of the condition and iscaused by a deficiency in the enzyme galactosamine-6-sul-phatase The gene involved with MPS IV A (GALNS) islocated on chromosome 16 MPS IV B is considered themilder form of the condition The enzyme, beta-galac-tosidase, is deficient in MPS IV B The gene involved withMPS IV B (GLB1) is located on chromosome 3

MPS VI (Maroteaux-Lamy syndrome)

MPS VI is caused by deficiency of the enzyme acetylglucosamine-4-sulphatase (arylsulfatase B), due tomutations in the ARSD gene located on chromosome 5.Affected individuals may have a mild or severe form of thecondition Typically, the nervous system and intelligenceare not affected Individuals with a more severe form ofMPS VI can develop airway obstruction,hydrocephalus

N-(extra fluid accumulating in the brain), and abnormalgrowth and formation of the bones Additionally, individ-uals with a severe form of MPS VI are more likely to diewhile in their teens With a milder form of the condition,individuals tend to be shorter than expected for their age,develop corneal clouding, and live longer

MPS VII (Sly syndrome)

MPS VII, an extremely rare form of MPS, resultsfrom a deficiency of the enzyme beta-glucuronidase due tomutations in the GUSB gene on chromosome 7 MPS VII

is also highly variable, but symptoms are generally lar to those seen in individuals with Hurler syndrome In

simi-severe cases, infants may be born with hydrops fetalis.

MPS IX (Hyaluronidase deficiency)

MPS IX is a condition that was first described in 1996and has been grouped with the other MPS conditions bysome researchers MPS IX is caused by the deficiency ofthe enzyme hyaluronidase due to mutations in the HYAL1gene on chromosome 3 In the few individuals describedwith this condition, the symptoms are variable, but somedevelop soft-tissue masses (growths under the skin) Also,these individuals are shorter than expected for their age

tory tests to establish an accurate diagnosis They may first

use a screening test that looks for glycosaminoglycans in

the urine The definitive diagnosis of an MPS is made

using a biochemical test that measures the specific enzyme

(known to be reduced or absent) in the individual’s tissues

or bodily fluids Genetic testing may also be used to

con-firm a suspected diagnosis and, in some cases, to provide

limited information about potential disease severity

Ge-netic testing is accomplished by looking for specific

changes known as mutations in the gene responsible for

the MPS disorder Genetic testing is available for all of the

MPS disorders except MPS IIIC, MPS IVB, and MPS IX

If the gene mutation(s) have been found in an affected

in-dividual, the same genetic test may be used for carrier

screening in unaffected family members, such as adult

sib-lings, and for prenatal diagnosis If the DNA mutations are

not found or if genetic testing is not available, carrier

screening and prenatal diagnosis may be accomplished

using biochemical methods Preimplantation genetic

di-agnosis (PGD) is available on a research basis for MPS I

and MPS II More information on PGD for these types of

MPS can be found by contacting the Reproductive

Genet-ics Institute at (773) 472-4900 or at rgi@flash.net

Treatment team

Treatment of MPS disorders requires a nary approach In addition to the patient’s primary health

multidiscipli-care professionals, medical professionals involved in the

care of patients with an MPS usually includes specialists in

neurology, neurosurgery, ophthalmology (eyes),

otolaryn-gology (ear-nose-throat), audiology (hearing), cardiology,

pulmonology (lungs), anesthesiology, gastroenterology,

nutrition, orthopedic surgery, rehabilitation (physical,

oc-cupational, and speech therapy) and genetics Some

pa-tients with MPS may receive comprehensive services

through a specialty clinic such as metabolic or

neuroge-netics clinic A genetic specialist, such as a clinical

geneti-cist or a genetic counselor, may be helpful to the patient

and family, especially at the time of diagnosis or prior to

genetic testing Psychological counseling and MPS

sup-port groups may also assist families in coping with this

condition

Treatment

Treatment of the MPS disorders primarily consists ofsupportive care and management of complications Bone

marrow transplant (BMT) and enzyme replacement are

two promising therapies that offer the possibility of

alter-ing the course of these conditions Due to the progressive

nature of the MPS disorders, regular evaluations by mary care providers and specialists is required to detectproblems early Treatment for the most common problemsfound in the MPS disorders is listed below

pri-Symmtomatic care and treatment

HYDROCEPHALUS Hydrocephalus (increased fluid inthe ventricles of the brain) commonly occurs in MPS I,MPS II, MPS VI, and MPS VII due to a blocked circulation

of cerebral spinal fluid in the brain If the hydrocephalus isdetected early, a surgical procedure known as ventricu-loperitoneal shunting or a VP shunt may afford the affectedindividual with a better outcome Periodic CT or MRI

scans may be recommended to monitor for hydrocephalus

in a child with MPS In MPS III, enlarged ventricles(spaces in the brain) may occur but here the enlargement isthought to be due to cortical atrophy (loss of brain cells)

It has been reported that shunting may decrease behaviorproblems associated with this form of MPS

SEIZURES Seizures are a problem found in severeforms of MPS and especially in MPS III (Sanfilippo syn-drome) Patients with seizures are given a type of pre-scription medication known as an anticonvulsant

VISION AND HEARING Regular evaluation by an thalmologist is recommended to look for common eyeproblems including changes in the retina, glaucoma, andcorneal clouding Retinal degeneration, an eye problemthat leads to night blindness and loss of peripheral vision,

oph-is common in MPS I, MPS II, and MPS III Adding a nightlight to a hall or bedroom may help with this Glaucoma

is especially common in MPS I and is usually treated withmedications Corneal clouding is found in MPS I, MPS IV,MPS VI and MPS VII People with corneal clouding havephotophobia (the inability to tolerate bright light) Capswith a visor or sunglasses may be recommended to helpreduce this problem Corneal transplantation is possiblefor people with significantly reduced vision yet transplantsmay not always result in improved vision in the long term.Hearing problems are common in the MPS disorders.Regular hearing evaluations are important so that childrenwith hearing loss can be treated early Hearing aids mayprovide some degree of improvement Recurrent otitismedia (middle ear infections) significantly contribute tohearing loss in individuals with MPS Prescription med-ications are used to treat otitis media Ventilating tubes inthe ears may be used to minimize the long term effects ofthese infections

CARDIOVASCULAR Many individuals with MPS showsome signs of heart disease Common problems includeabnormal heart valves, narrowing of the blood vessels inthe heart, and weak heart muscles (cardiomyopathy) Pa-tients with MPS I H and the severe form of MPS II usually

have damage to the mitral valve In MPS I H/S, MPS IS,

MPS IV, and MPS VI, aortic valvular disease is more

com-mon Medications may be prescribed for congestive heart

failure and hypertension associated with underlying heart

disease Valve replacement surgery is possible and has

been reported in the MPS disorders

AIRWAY DISEASE Obstruction of the airway is a mon and significant problem for individuals with MPS

com-This problem can be due to a narrowed trachea (wind

pipe), thickened vocal cords, large adenoids or tonsils,

de-creased rib movement with breathing, and a large tongue

A condition known as obstructive sleep apnea (temporary

cessation of breathing while asleep) is the most common

airway problem in MPS Treatment for sleep apnea may

include: removal of adenoids and tonsils, CPAP or BiPAP

treatment, or a tracheostomy CPAP (continuous positive

airway pressure) and BiPAP (bilevel positive airway

pres-sure) are treatments that help to keep the airway open at

nighttime A tracheostomy, an permanent opening through

the neck into the trachea, may be needed in severe cases of

sleep apnea

FEEDING PROBLEMSFor many individuals with MPS,neurological problems eventually lead to significant prob-

lems with chewing and swallowing Surgical placement of

gastrostomy tube (G-tube) or a jejunostomy tube (J-tube)

may be recommended when feeding problems cause

weight loss, choking, gagging, or episodes of pneumonia

SKELETAL DEFORMITIES Bony problems, especially ofthe neck, spine, and hips may require orthopedic inter-

vention Problems of the cervical spine due to odontoid

hypoplasia (improper formation bones that stabilize the

head and neck) can be quite serious Odontoid hypoplasia

can lead to slippage of the bones in the neck and

com-pression of the spine in the cervical (neck) region In

se-vere cases, this spinal cord compression may result in

nerve damage, paralysis or death Odontoid hypoplasia is

common in MPS IV (Morquio syndrome) Treatment

in-cludes regular monitoring with MRI or X-rays and

cervi-cal fusion surgery for severe cases Other bony problems

seen in the MPS disorders include progressive scoliosis or

kyphosis (curvatures of the spine ) and hip dysplasia

(ab-normal hip joint) Bracing and sometimes surgery may be

used to treat spine curvature A surgical procedure known

as spinal fusion may be considered in patients with

sig-nificant curvature Patients with hip dysplasia may be

given non-steroidal anti-inflammatory medications

CARPAL TUNNEL SYNDROME Carpal tunnel drome is a common problem in MPS Although many in-

syn-dividuals with MPS may not have typical symptoms

(numbness, tingling,pain), the carpal tunnel syndrome

can and may be severe Treatment options include

splint-ing, anti-inflammatory medications and surgery

Bone marrow transplantation (BMT)

Bone marrow transplants have been used to treat dren with MPS I, MPS II, MPS III, and MPS VI Somesuccess has been achieved with BMT in MPS I and inMPS VI; however, this treatment is not a cure and is con-sidered experimental due to the associated risks, includingdeath Some children who have undergone BMT haveshown reduced progression of some disease symptoms Itremains uncertain whether BMT can prevent brain dam-age BMT is not recommended as a treatment for MPS II

chil-or MPS III

Enzyme replacement therapy

Enzyme replacement therapy is available for MPS I

A pharmaceutical form of alpha-L-iduronidase known aslaronidase is available in the United States More infor-mation may be obtained at<http://www.aldurazyme.com>.Enzyme therapy may be an option in the future for indi-viduals with MPS IV

Recovery and rehabilitation

Rehabilitation for the MPS disorders consists of ical, occupational, and possibly speech therapy For ex-ample, physical therapy may help preserve joint functionfor individuals with joint stiffness Joint stiffness is pres-ent in all of the MPS disorders except MPS IV and MPS

phys-IX In physical therapy, patients may undergo motion exercises (passive bending and stretching of thearms and legs) Also, physical therapy after neck, spine orknee surgery can help patients (who could walk prior tosurgery) to walk again Occupational therapy can teach pa-tients to use adaptive techniques and devices that may helpcompensate for loss of mobility and/or for loss of speech.Speech therapy may be indicated for individuals withMPS; however, this intervention may not be useful in cases

range-of-in which the mental condition is rapidly deterioratrange-of-ing.Hyperactivity can be a severe problem in individualswith MPS, especially in MPS III and MPS II Medicationsmay or may not be successful in treating this problem Be-havior modification programs may be helpful for some hy-peractive MPS children It may also be necessary to adaptthe house and yard to the child

Clinical trials

As of December 2003, there were fourclinical trials

related to the MPS disorders that were recruiting patients

A phase II/II trial to determine whether the administration

of iduronate-2-sulfatase enzyme is safe and efficacious inpatients with MPS II will be conducted in the UnitedStates, Brazil, Germany and England Information on thistrial can be found at <http://www.clinicaltrials.gov> or bycontacting Transkaryotic Therapies at 617-613-4499 A

phase III trial to evaluate the ability of recombinant human

arylsulfatase B enzyme to enhance endurance in patients

with Mucopolysaccharidosis VI (MPS VI) will be

con-ducted in the United States Information on this trial can

be found at <http://www.clinicaltrials.gov> or by

con-tacting BioMarin Pharmaceuticals at 415-884-6700 A

phase II study of allogeneic bone marrow or umbilical

cord blood transplantation in patients with

mucopoly-saccharidosis I will be conducted in the United States

Information on this trial can be found at <http://www

clinicaltrials.gov> or by contacting the Study Chair at the

Fairview University Medical Center in Minneapolis,

Min-nesota, at 612-624-5407 A phase II study of bone marrow

or umbilical cord blood transplantation in patients with

lysosomal or peroxisomal inborn errors of metabolism

In-formation on this trial can be found at

<http://www.clini-caltrials.gov> or by contacting the Study Chair at the

Fairview University Medical Center in Minneapolis,

Min-nesota at 612-624-5407

Prognosis

Life expectancy for individuals with an MPS is tremely varied In severe forms of MPS, affected individ-

ex-uals may die in infancy such as in the severe cases of Sly

syndrome, or they may die in in childhood or adolescence

such as in Hurler syndrome and severe Hunter syndrome

In milder forms of MPS such as Scheie syndrome, mild

Hunter syndrome individuals can live well into adulthood

Life spans for individuals with Sanfillipo syndrome,

Maroteaux-Lamy syndrome, Morquio syndrome and mild

Sly syndrome are quite variable As more MPS I patients

utilize enzyme replacement therapy, new information

about prognosis and life span for this disorder will be

learned

Special concerns

Many individuals with an MPS condition have lems with airway constriction This constriction may be so

prob-serious as to create significant difficulties in administering

general anesthesia Therefore, it is recommended that

sur-gical procedures be performed under local anesthesia

whenever possible If general anesthesia is needed, it

should be administered by an anesthesiologist experienced

in the MPS disorders

Children and families affected by an MPS may fit from social services A social worker may be able to

bene-help families obtain Social Security, Medicaid, or other

as-sistance available from agencies that specialize in the care

of persons with disabilities A child with MPS may

bene-fit from an Individual Education Plan (IEP) An IEP

provides a framework from which administrators,

teach-ers, and parents can meet the educational needs of a childwith MPS

Resources BOOKS

Neufeld, Elizabeth F and Joseph Muenzer.“The

Mucopolysaccharidoses.” Chapter 136 In The Metabolic

and Molecular Bases of Inherited Disease, 8th ed., Vol 3,

edited by Charles R Scriver, Arthur L Beaudet, William

S Sly, and David Valle New York: McGraw-Hill Medical Publishing Division, 2001.

Parker, James N., and Philip M Parker, eds The Official

Parent’s Sourcebook on Mucopolysachharidoses: A Revised and Updated Directory for the Internet Age San

Diego, CA: ICON Health Publications, 2002.

Gulati, M S., and M A Agin “Morquio syndrome: a

rehabili-tation perspective.” Journal of Spinal Cord Medicine 19

(January 1996): 12–16.

Kakkis, E D “Enzyme replacement therapy for the

mucopolysaccharide storage disorders.” Expert Opinion

on Investigational Drugs 11 (May 2002): 675–685.

Robertson, S P., G L Klug, and J G Rogers “Cerebrospinal fluid shunts in the management of behavioral problems in

Sanfilippo syndrome.” European Journal of Pediatrics

157 (August 1998): 653–655.

Vougioukas, V I., A Berlis, M V Kopp, R Korinthenberg, J Spreer, and V van Velthoven “Neurosurgical interven- tions in children with Maroteaux-Lamy syndrome Case

report and review of the literature.” Pediatric

The National Institute of Neurological Disorders and Stroke

(NINDS) Mucopolysaccharidoses Information Page.

<http://www.ninds.nih.gov/health_and_medical/

disorders/mucopolysaccharidoses.htm>.

OTHER

The National MPS Society MPS Disorder booklets 45

Packard Drive, Bangor, ME: The National MPS Society, 2001-2003 <http://www.mpssociety.org/lib-health.html>.

Society for Mucopolysaccharide Diseases 46 Woodside Road,

Amersham, Buckinghamshire HP6-6AJ, UK (149) 4252; Fax: (149) 443-4252 mps@mpssociety.co.uk.

443-<http://www.mpssociety.co.uk>.

Dawn J Cardeiro, MS, CGC

Definition

Multi-infarctdementia is one form of dementia that

occurs when small blood vessels in the brain are blocked

by blood clots or fatty deposits The blockage interrupts the

flow of blood to regions of the brain (astroke), which, if

sustained, causes the death of cells in numerous areas of the

brain Another form of multi-infarct dementia is inherited

Description

Blockage or narrowing of small blood vessels byblood clots or by deposits of fat can impede the flow of

blood through the vessel Deprivation of the essential blood

is catastrophic for the regions that are supplied by the

ves-sels In the brain, such vessel blockage can cause the death

of brain cells This event is also called a stroke The

stroke-related cell death affects the functioning of the brain

Multi-infarct dementia is the most common form ofdementia (the loss of cognitive brain due to disease or in-

jury) due to changes in blood vessels.Alzheimer’s

dis-ease is the most common of these so-called vascular

dementias The term multi-infarct is used because there

are many areas in the brain where cell damage or death

occurs Besides dementia, multi-infarct dementia can

cause stroke, headaches of migraine-like intensity, and

affects men more than women Multi-infarct dementia is

the second most common cause of dementia in older

peo-ple after Alzheimer’s disease, accounting for up to 20% of

all progressively worsening dementias

CADASIL occurs in young male and female adults Ithas been diagnosed in Americans, Africans, and Asians,

and may occur in other racial groups

Causes and symptoms

The root cause of multi-infarct dementia is usuallysmall blood clots that lodge in blood vessels in the brain,which results in the death of brain cells Over time, the se-ries of small strokes (also known as mini-strokes, transientischemic attacks, or TIAs) magnifies the brain cell dam-age Blood clots can result from an elevated blood pres-sure Indeed, it is uncommon for someone affected withmulti-infarct dementia not to have a history of high bloodpressure

There are a variety of symptoms caused by the braincell loss These include mental confusion, problems re-taining information even for a short time, loss of recogni-tion of surroundings that are familiar (which can lead togetting lost in previously familiar territory), loss of control

of urination and defecation, moving with a rapid shufflingmotion, difficulty in following instructions, rapid swings

in emotion, and difficulty performing tasks that were viously routine These symptoms appear in a stepwisemanner, from less to more severe As well, the initialsymptoms can be so slight as to be unrecognized, disre-garded, or rationalized as being due to other causes such

pre-as a temporarily stressful period These early problems clude a mild weakness in an arm or a leg, slurred speech,

in-or dizziness that only lasts for a few days As more blood

vessels become blocked with the occurrence of morestrokes, the more severe symptoms associated with men-tal decline become apparent

CADASIL is characterized by a series of strokes,which is thought to be triggered by genetically determineddeficiencies of small cerebral arteries The defects affectblood flow to the brain in a similar fashion as occurs inmulti-infarct dementia The symptoms associated withCADASIL range from migraines to a slowly progressingseries of symptoms that is similar to the symptoms that de-velop in multi-infarct dementia

Diagnosis

Multi-infarct dementia is diagnosed based on the tory of symptoms, especially of high blood pressure andstrokes A physician will look for several features duringthe examination, which include arm or leg weakness,speech difficulties, or dizziness Tests that can be per-formed in the doctor’s office include taking a bloodpressure reading, recording the heartbeat (an electro-encephalogram, or EEG), and obtaining blood for labora-tory analysis Ultrasound studies of the carotid artery mayalso be performed

his-Diagnosis most often involves the non-destructive aging of the brain by means of computed tomography (CT)

im-ormagnetic resonance imaging (MRI) to reveal blood

clots or the characteristic damaged regions of the brain

Key TermsDementia A chronic loss of mental capacity due

to an organic cause

Infarct Tissue death due to lack of oxygen

result-ing from a blood clot, plaque, or inflammation that

blocks an artery

Transient ischemic attack (TIA) A temporary,

stroke-like event that lasts for only a short time and

is caused by a blood vessel that is temporarily

blocked

Diagnosis can also be aided by an examination by apsychologist or a psychiatrist to test a person’s degree of

mental reasoning, ability to learn and retain new

informa-tion, and attention span Symptoms can be similar to those

of Alzheimer’s disease, which can complicate and delay the

diagnosis of both disorders Indeed, a person can have both

disorders at the same time, as their causes are different

Treatment team

A person with multi-infarct dementia can benefit from

a support network that includes a family physician,

neu-rologist, pharmacist, nurses, and supportive family

mem-bers and other care givers Community resources are also

important, such as assisted living facilities, adult day or

respite care centers, and local agencies on aging.

Treatment

There is no specific treatment for multi-infarct mentia, as the damage to the brain cells cannot be re-

de-versed Treatment typically involves trying to limit further

deterioration This focuses on establishing and/or

main-taining a lower blood pressure, which lessens the tendency

of blood clot formation Those people who are diabetic

will be treated for this condition, as diabetes can contribute

to stroke Other factors that can be involved in lessening

blood pressure include maintaining a target cholesterol

level,exercise, avoiding smoking, and moderation in

al-cohol consumption

Aspirin is known to reduce the tendency of the blood

to clot Some physicians will prescribe aspirin or similarly

acting drugs for this purpose As well, those with high

cho-lesterol may benefit from a diet change and/or the use of

cholesterol-lowering drugs such as statins In some people,

surgery that removes blockages in the main blood vessel

to the brain (the carotid artery) can be done Other

surgi-cal treatments that increase blood flow through vessels

in-clude angioplasty and stenting to increase arterial flow to

the brain

Recovery and rehabilitation

As damage to the brain cannot be reversed, the focusfor a person with multi-infarct dementia is placed uponprevention of further brain tissue injury, and maintainingoptimum independent functioning

Clinical trials

As of May 2004, there were no clinical trials

under-way or in the process of recruiting patients for eithermulti-infarct dementia or CADASIL However, research isbeing funded by agencies such as the National Institute ofNeurological Disorders and Stroke and is aimed at under-standing the development of dementia The hope is that thediagnosis of dementias will be improved Ultimately, thegoal is to reverse or prevent the disorder

Prognosis

The outlook for people with multi-infarct dementia ispoor While some improvement in mental faculty mayoccur, this is typically of short-term duration Over longertime, mental decline is inevitable and marked

Special concerns

A person with multi-infarct dementia is often reliant

on family and friends for daily care and support Familyand caregivers can help by stimulating a person’s mentalactivity and prompting the individual to recall past expe-riences Eventually, around-the-clock care may becomenecessary to provide a safe and stimulating environment

Resources BOOKS

Bird, T D “Memory Loss and Dementia.” In Harrison’s

Principles of Internal Medicine, 15th Edition, edited by

Franci, A S., E Daunwald, and K J Isrelbacher New York: McGraw Hill, 2001.

Mace Nancy L The 36-Hour Day: A Family Guide to Caring

for Persons with Alzheimer Disease, Related Dementing Illnesses, and Memory Loss in Later Life New York:

Warner Books, 2001.

OTHER

“Multi-Infarct Dementia.” National Mental Health

Association May 14, 2004 (June 1, 2004).

<http://www.nmha.org/infoctr/factsheets/102.cfm>.

“Multi-Infarct Dementia Fact Sheet.” Alzheimer’s Disease

Education & Referral Center (ADEAR) May 15, 2004

(June 1, 2004) <http://www.alzheimers.org/

pubs/mid.htm>.

“NINDS Multi-Infarct Dementia Information Page.” National

Institute of Neurological Disorders and Stroke May 14,

2004 (June 1, 2004) <http://www.ninds.nih.gov/

health_and_medical/disorders/multi-infarctdementia.doc>.

Multifocal motor neur

y ORGANIZATIONS

National Institute for Neurological Diseases and Stroke

(NINDS) P.O Box 5801, Bethesda, MD 20824 (301) 496-5751 (800) 352-9424 <http://www.ninds/nih.gov>.

National Institute on Aging (NIA) 31 Center Drive,

Brian Douglas Hoyle, PhD

otrophic lateral sclerosis (ALS) Unlike ALS, however,

multifocal motor neuropathy can be treated; therefore,

dis-tinguishing between these two conditions is crucial

Demographics

Multifocal motor neuropathy is a very rare condition,affecting only about 1 per 100,000 people in the popula-

tion Men are about three times as likely to be affected as

women Most patients are between the ages of thirty and

fifty when symptoms are noted, with the average age of

onset being 40 years

Causes and symptoms

Multifocal motor neuropathy is thought to resultfrom an autoimmune disorder; that is, the body’s immune

system accidentally misidentifies markers on the body’s

own nerve cells as foreign The immune system then

be-gins to produce cells that attack and injure or destroy

ei-ther the nerve cells or the myelin sheath wrapped around

the nerve cells Because the myelin sheath allows

mes-sages to be conducted down a nerve quickly, injury to the

sheath or to the nerve itself results in slowed or faulty

Diagnosis

Diagnosis of multifocal motor neuropathy usually quires both a careful physical examination, as well as elec-tromyographic (EMG) testing Physical examination willreveal weakness and decreased muscle size, abnormal re-flexes, muscle twitches, and totally normal sensation EMGinvolves inserting a needle electrode into a muscle, andmeasuring the electrical activity within the muscle at restand during use A characteristic pattern of abnormal nerveconduction and muscle contraction will be noted on EMG.Blood tests will usually reveal the presence of anti-bodies (immune cells) directed against ganglioside, a com-ponent of nerve cells

In very mild, early cases, treatment may not be essary If the condition progresses or prompts serious dis-ability, treatment may be necessary Treatment may then berequired intermittently, if the condition progresses again

nec-Prognosis

Muscle strength usually begins to improve withinthree to six weeks of the initiation of treatment Earlytreatment of multifocal motor neuropathy usually results

in sufficient symptom resolution to prevent any permanentdisability Over many years, however, many patients willnote a continued, slow progression of muscle weakness

Resources BOOKS

Asbury, Arthur K., and Stephen L Hauser “Guillain-Barré Syndrome and Other Immune-mediated Neuropathies.”

In Harrison’s Principles of Internal Medicine, edited by

Eugene Braunwald, et al NY: McGraw-Hill Professional, 2001.

Multiple scler

Griffin, John W “Immune Mediated Neuropathies.” In Cecil

Textbook of Internal Medicine, edited by Lee Goldman, et

al Philadelphia: W B Saunders Company, 2000.

Shields, Robert W., and Asa J Wilbourn “Demyelinating

dis-orders of the peripheral nervous system.” In Textbook of

Clinical Neurology, edited by Christopher G Goetz.

Philadelphia: W B Saunders Company, 2003.

WEBSITES

National Institute of Neurological Disorders and Stroke

(NINDS) NINDS Multifocal Motor Neuropathy

Information Page November 1, 2003 (June 3, 2004).

sults in injury to the myelin sheath (the fatty matter that

covers the axons of the nerve cells), the oligodendrocytes

(the cells that produce myelin) and, to a lesser extent, the

axons and nerve cells themselves The symptoms of

mul-tiple sclerosis vary, depending in part on the location of

plaques (areas of thick scar tissue) within the central

nerv-ous system Common symptoms include weakness and

fa-tigue, sensory disturbances in the limbs, bladder or bowel

dysfunction, problems with sexual function, and ataxia

(loss of coordination) Although the disease may not be

cured or prevented at this time, treatments are available to

reduce severity and delay progression

Description

Multiple, or disseminated, sclerosis (MS) is a slowlyprogressive disease of the central nervous system (CNS),

that comprises the brain and spinal cord In 1868, French

physician Jean-Martin Charcot (1825–1893) produced his

lectures on “Sclerose en plaques,” providing the first

de-tailed clinical description of the disease The cause of

mul-tiple sclerosis is unknown, and it cannot be prevented or

cured Great progress, however, is being made in treating

and identifying underlying mechanisms that trigger the

disease The primary characteristic of MS is the

destruc-tion of myelin, a fatty insuladestruc-tion covering the nerve fibers

The end results of this process, called demyelination, are

multiple patches of hard, scarred tissue called plaques

Another important feature in the disease is destruction of

axons, the long filaments that carry electric impulses away

from a nerve cell, which is now considered to be a major

factor in the permanent disability that occurs with MS

Multiple sclerosis is usually characterized by a lapsing remitting course in the early stages, with full ornearly full recovery initially In the early stages, there may

re-be little damage to axons Over time, the disease enters anirreversible progressive phase of neurological deficit Eachrelapse causes further loss of nervous tissue and progres-sive dysfunction In some cases there may be chronic pro-gression without remission or acute disease rapidly leading

After several years, the majority (70%) of personswith MS will develop secondary progressive multiple scle-rosis (SPMS), whereby they experience a progressive neu-rological deterioration They may still suffer fromsuperimposed relapses A subcategory of RRMS patients(around 20%) has benign MS These patients have rareand mild relapses and a long course of disease with mini-mal or no disability If patients have a steady neurologicaldecline from the onset, without relapses, they are de-scribed as having primary-progressive multiple sclerosis(PPMS) This comprises approximately 15–20% of peoplewith the disease

A fourth, rare type of MS is progressive-relapsingmultiple sclerosis (PRMS), which is considered a variant ofPPMS with similar prognosis In patients with PRMS,there is a gradual neurological decline from the beginning

It is similar to PPMS, but has superimposed, acute relapses

There is a variation in the worldwide distribution of

MS, with the highest prevalence in the northern and tral Europe, northern North America and southeastern

MS results in injury to the myelin sheath that covers the axons of the nerve cells, the cells that produce myelin

(oligoden-drocytes), and, to a lesser extent, the axons and nerve cells themselves (Illustration by Electronic Illustrators Group.)

Australia Clusters, or areas with more than the expected

amount, occur There are also racial differences, with a low

prevalence in Asians and Africans or people of African

de-scent, and a higher frequency in Caucasians, especially of

northern European descendent MS is rare between the

equator and latitudes 30°–35° north and south The

preva-lence of MS increases proportionally with increased

dis-tance from the equator There is no satisfactory explanation

of this phenomenon, although certain variables have been

researched These include environmental factors, such as

climate, humidity, hours of daily sunshine, resistance to

certain viruses, and even consumption of cow’s milk

Causes and symptoms

The causes of multiple sclerosis remain unknown, but

it is widely accepted that susceptibility to MS is

deter-mined by a complex interaction between susceptibility

genes and environment The most popular current theory

is that the disease occurs in people with a genetic tibility, who are exposed to some environmental assault (avirus or a toxin) that disrupts the blood-brain barrier, aprotective membrane that controls the passage of sub-stances from the blood into the central nervous system.Most researchers consider MS to be an autoimmune dis-ease-one in which the body, through its immune system,launches a defensive attack against its own tissues Im-mune factors converge in the nerve cells and trigger in-flammation and an autoimmune attack on myelin andaxons Still, a number of disease patterns have been ob-served in MS patients, and some experts believe that MSmay prove to be not a single disorder, but may representseveral diseases with different causes

suscep-Components of myelin such as myelin basic proteinhave been the focus of much research because, when in-jected into laboratory animals, they can precipitate exper-imental allergic encephalomyelitis (EAE), a chronic

Multiple scler

relapsing brain and spinal cord disease that resembles MS

The injected myelin probably stimulates the immune

sys-tem to produce anti-myelin T-cells that attack the animal’s

own myelin

Increasing scientific evidence suggests that geneticsmay play a role in determining a person’s susceptibility to

MS No specific gene has been identified and it seems to

have a mode of inheritance that involves multiple genes

Twin studies have shown an increased risk of 30% in

iden-tical twins, and around 5% in fraternal twins First-degree

relatives of a person with MS have a two or three percent

increased risk, which, although small, is higher than in the

general population Further indications that more than one

gene is involved in MS susceptibility comes from studies

of families in which more than one member has MS

Several research teams found that people with MS herit certain regions on individual genes more frequently

in-than people without MS Of particular interest is the

human leukocyte antigen (HLA) or major

histocompati-bility complex region on chromosome 6 HLAs are

ge-netically determined proteins that influence the immune

system Another interesting candidate is CD24, which has

shown to be essential for the induction of EAE in mice

CD24 is a cell surface protein with expression in a variety

of cell types that can participate in the rise of MS,

includ-ing activated T-cells

An infectious cause of MS has been indicated bysome studies as well as by similarities to infectious de-

myelinating diseases However, infectious agents more

likely shape the immune response that may induce the

dis-ease under special circumstances Evidence is mounting

that infection with the Epstein-Barr virus (EBV), which

can cause mononucleosis, may also increase the risk of

de-veloping multiple sclerosis later in life Researchers have

shown that people with multiple sclerosis tend to carry

higher levels of antibodies to the Epstein-Barr virus and

that they seem to be at higher risk for the disease Some of

the immune cells that become programmed to attack the

Epstein-Barr virus may begin to attack myelin as well

Environmental factors, other than infectious agents,for which there is some evidence of an association with

MS, include toxins, low sunlight exposure, diet factors,

and trauma

Almost any neurological deficit can occur in MS, butthere are several signs and symptoms that are characteris-

tic and their presence should suggest MS as a possible

di-agnosis, particularly in a young adult

Vision disorders such as optic neuritis can occur Opticneuritis (ON) is an inflammation of the optic nerve char-

acterized by acute or subacute loss of vision usually in one,

but occasionally in both eyes The visual loss evolves over

a period of hours or days Vision returns to normal within

two months, but may deteriorate in later years Previoushistory of optic neuritis in a person who develops a neuro-logical illness will strongly support the diagnosis of MS.Cognitive (thought) impairment is thought to affect40–70% of MS patients and can be present even in theearly stages of MS Approximately one-third of peoplewith MS have some degree of memory loss Other areas ofcognitive function particularly affected in the MS patientinclude sustained attention, verbal fluency, and spatial per-ception Dementia (loss of intellectual function) is often

common in the latter stages of MS

Many MS patients are temperature sensitive In ter weather or during a period of raised body temperature,their MS symptoms worsen Most frequently, vision is af-fected and muscle weakness occurs

hot-About two-thirds of MS patients experience pain at

some point during the course of the disease and 40% arenever pain free MS causes many pain syndromes; someare acute, while others are chronic Some worsen with ageand disease progression Pain syndromes associated with

MS are trigeminal (facial) pain, powerful spasms andcramps, optic neuritis pain, pressure pain, stiffened joints,and a variety of sensations including feelings of itching,burning, and shooting pain

The Lhermitte’s sign can occur, which is actuallymore of a symptom than a sign A tingling or electric-likesensation down the back and legs is felt upon flexing theneck The symptom is non-specific, but occurs more fre-quently in MS than in any other condition and provides animportant clue to the correct diagnosis

Urinary incontinence affects up to 90% of people withmultiple sclerosis and usually occurs before major physi-cal disability is apparent Bladder problems are due toplaques in the spinal cord If demyelination occurs in bothcontrolling pathways, the bladder will neither store urinenor empty it properly Constipation affects about 40% ofpeople with MS Bowel incontinence and urgency of defe-cation can also occur in about half of people with MS.Fatigue is a common complaint in MS Characteris-tics of fatigue include muscle weakness, coordinationproblems, ataxia, transient deafness, changes in taste orsmell and numbness of the extremities Spasticity occurs

in up to 90% of MS patients and it can be painful and tressing Spasticity is characterized by weakness, loss ofdexterity, and the inability to control specific movements

dis-It is usually more severe in the legs and torso

Sexual dysfunction is common among people withmultiple sclerosis If MS damages the nerve pathwaysfrom the brain to the sexual organs via the spinal cord, sex-ual response can be directly affected Physicians and peo-ple with MS often neglect to deal with this aspect of the

Multiple scler

Autoimmune disease One of a group of diseases,

like rheumatoid arthritis and systemic lupus matosus, in which the immune system is overactiveand has lost the ability to distinguish between selfand non-self The body’s immune cells turn on thebody, attacking various tissues and organs

erythe-Axon A long, threadlike projection that is part of

a neuron (nerve cell)

Myelin A fatty sheath surrounding nerves

through-out the body that helps them conduct impulsesmore quickly

disease, and both treatments and strategies for success are

available

Depression is common in MS; some studies show

that over 50% of people with MS have depression at some

point in their lifetime There is also an increased risk of

suicide If depression is present, it should be treated prior

to initiating MS therapy Depression in those with MS is

treated in the same way as the general population

Diagnosis

MS diagnosis is based upon an individual’s history ofclinical symptoms and neurological examination A qual-

ified physician, often a neurologist, must thoroughly

re-view all symptoms experienced by an individual to suspect

MS Other conditions with similar symptoms must be

ruled out, often requiring various tests

The diagnosis of MS is usually made in a young adultwith relapsing and remitting symptoms referable to dif-

ferent areas of CNS white matter Diagnosis is more

dif-ficult in a patient with the recent onset of neurological

complaints or with a primary progressive clinical course

Laboratory studies include blood work to excludecollagen vascular disease, infections (ie,Lyme disease,

syphilis), endocrine abnormalities, vitamin B-12

defi-ciency, sarcoidosis, andvasculitis The examination of

cerebrospinal fluid (CSF) has been used to support the

di-agnosis of MS The presence of myelin basic protein in

the CSF of an MS patient may be highly suggestive of

ac-tivity of the MS process, but its absence does not rule out

active disease

A newer neuroimaging technique, magnetic nance spectroscopy (MRS), has been useful in following

reso-NAA (N-acetyl-aspartate) levels in patients with multiple

sclerosis NAA is an amino acid found in neurons and

axons of the mature brain In patients with mitting MS, NAA levels are reduced, suggesting axonalloss; however, in patients with secondary progressive MSwith more disability, the NAA levels are reduced more sig-nificantly In fact, patients with MS had lower levels ofNAA even in areas of the brain previously thought to beunaffected, when compared with levels in normal persons

relapsing-re-Magnetic resonance imaging (MRI) remains the

imaging procedure of choice for diagnosing and ing disease progression in the brain and spinal cord Thistest can show brain abnormalities in 90–95% of patientsand spinal cord lesions in up to 75% of cases, especially

monitor-in elderly patients However, MRI alone cannot be used todiagnose MS Evoked potential tests that measure howquickly and accurately a person’s nervous system re-sponds to certain stimulation have been the most usefulneurophysiological studies for evaluation of MS

At the onset, MS may be mistaken for other matory diseases of the central nervous system, such asBehçet disease, antiphospholipid syndrome or acute dis- seminated encephalomyelitis (ADEM) Pseudotumoral

inflam-MS may be reminiscent of lymphoma, other tumors (glialtumors), or infectious diseases (like Lyme disease, HTLV1infection or abcess) Recurrent relapses of neurologicalimpairment may also be mistaken for cavernomatosis Inmost cases, MRI findings, cerebrospinal fluid analysis,evoked potentials, the association with systemic signs andthe relapsing remitting nature of the disease allow physi-cians to exclude other diseases, and to arrive at a diagno-sis of MS

Treatment team

The multidisciplinary team usually includes ists in neurology, urology, ophthalmology, neuropsychol-ogy, and social work

special-Treatment

The three goals of drug therapy in the treatment of

MS are management of acute episodes, prevention of ease progression, and treatment of chronic symptoms.Specific symptoms that may be treated include musclespasticity, lack of co-ordination, tremor, fatigue, pain,bladder and bowel dysfunctions, sexual dysfunction anddepression

dis-Exacerbations (episodes of worsening symptoms) can

be defined as temporary flare-ups, sometimes referred to

as attacks or relapses Most relapses show a degree ofspontaneous recovery, but treatment is offered for those re-lapses that have a severe impact on function Steroids arethe treatment of choice for relapses, usually methyl-pred-nisolone given orally or by intravenous infusion Beforestarting steroids, infection should be excluded because

Multiple scler

steroids have immunosuppressant action and can

exacer-bate the infection

Disease modifying treatments are aimed at slowingdisease progression The two current types of im-

munomodulatory agents used as a first line treatment are

interferon beta and glatiramer acetate Interferon beta has

proved effective with RRMS and SPMS There is currently

no evidence for improvement with PPMS Discontinuation

of the treatment may be necessary because of intolerance

to side effects, when a pregnancy is planned, or when it is

no longer effective Glatiramer is the appropriate treatment

to reduce relapse frequency in patients with RRMS and it

should not be used for both PPMS and SPMS Stopping

criteria for glatiramer are the same of interferon beta

A number of treatments are available for managing

MS chronic symptoms and complications, each one with

specific drugs Indeed, symptomatic treatment, along with

supportive measures and rehabilitation, are a major part of

the MS treatment

Recovery and rehabilitation

When recovering from a symptom flare-up or ing to cope with a change in mobility, rehabilitation

learn-through physical therapy can be of great value training

pa-tients to improve mobility and to decrease spasticity and

strengthen muscles Some of those who have a physically

demanding or highly stressful job may choose to make a

career change, in which case vocational training is helpful

Occupational therapy helps in assessing the patient’sfunctional abilities in completing activities of daily living,

assessing fine motor skills, and evaluating for adaptive

equipment and assistive technology needs Speech

thera-pists assess the patient’s speech, language, and

swallow-ing and may work with the patient on compensatory

techniques to manage cognitive problems

Clinical trials

The National Institute of Neurological Disorders andStroke (NINDS) is recruiting patients to evaluate the safety,

tolerability, and effect of the drug Rolipram on MS The

NINDS is also recruiting patients with

relapsing-remitting or secondary progressive multiple sclerosis to

examine the safety and effectiveness of Zenapax (a

labo-ratory-manufactured antibody) in treatment of MS More

information is available at the website: <http://www

clinicaltrials.gov>, a clinical trial service sponsored by the

United States government

Prognosis

It is generally very difficult to predict the course of

MS The disorder varies greatly in each individual, but

most people with MS can expect to live 95% of the normal

life expectancy Some studies have shown that people whohave few attacks in the first several years after diagnosis,long intervals between attacks, complete recovery from at-tacks, and attacks that are sensory in nature (i.e., numbness

or tingling) tend to fare better People who have earlysymptoms of tremor, difficulty in walking, or who havefrequent attacks with incomplete recoveries, or more le-sions visible on MRI scans early on, tend to have a moreprogressive disease course

Special concerns

People with should avoid caffeine-containing age, which can actually be dehydrating The diet shouldalso be rich in fiber, particularly from whole grains, fruitsand vegetables to increase digestive motility and reduceconstipation Maintenance of weight in the normal range

bever-is also desirable in order to diminbever-ishes stress on the jointsand skeletal muscles

Gait difficulty (difficulty with walking) may worsenduring pregnancy, and assistive devices for walking or awheelchair are useful at this time During pregnancy, blad-der and bowel problems may also be aggravated in womenwith MS who already have these dysfunctions

Resources BOOKS

O’Connor, Paul Multiple Sclerosis: The Facts You Need.

Firefly Books, 1999.

Warren, Sharon, and Kenneth Warren Multiple Sclerosis.

World Health Organization, 2001.

PERIODICALS

Myles, Mary L “The ongoing battle against multiple

sclero-sis.” Canadian Journal of Diagnosis (June, 2003):

108–117.

OTHER

“About MS.” Multiple Sclerosis Association of America.

<http://www.msaa.com> (February 12, 2004).

National Institute of Neurological Disorders and Stroke.

NINDS Multiple Sclerosis Information Page.

<http://www.nationalmssociety.org>.

Marcos do Carmo OyamaIuri Drumond Louro

Multiple system atr

Key TermsAtrophy The progressive wasting and loss of func-

tion of any part of the body

Cerebellum The part of the brain involved in the

coordination of movement, walking, and balance

Neurodegeneration The deterioration of nerve

symptoms include tremor, rigidity and slowed movements;

cerebellar symptoms include incoordination and

un-steady gait; and autonomic symptoms include orthostatic

hypotension (drop in blood pressure upon standing) and

urinary incontinence Because of this wide variety of

symptoms, it was originally thought of as three distinct

diseases: striatonigral degeneration (parkinsonian

symptoms), olivopontocerebellar atrophy (cerebellar

symptoms) and Shy-Drager syndrome (autonomic

symp-toms) Further study showed the overlap among these

con-ditions was best explained by considering them as a single

disease with symptoms clustered into three groups

His-torically, confusion about the disease was made even

worse because olivopontocerebellar atrophy is also the

name of an unrelated genetically inherited disease It is

hoped that widespread use of the name MSA will clear up

some of this confusion

Demographics

Because MSA is often misdiagnosed, figures on itsprevalence are not known with certainty It is estimated

there are between 25,000 and 100,000 people in the United

States with MSA Onset is usually in the early fifties, and

men are slightly more likely to be affected than women

Causes and symptoms

The cause or causes of MSA are unknown No geneshave been found for MSA Some evidence indicates that

toxins may be responsible, but no specific agents have

been identified The brains of MSA patients reveal that

cells called glia undergo characteristic changes Glia are

supportive cells for neurons, brain cells that conduct

elec-trical signals In MSA, glia develop tangles of proteins

within them, called glial cytoplasmic inclusions It is not

known whether these actually cause MSA, or are caused

by some other problem that is the real culprit

The symptoms of MSA fall into three separate parkinsonism, cerebellar symptoms, and autonomic dis-

areas-turbances The distribution and severity of individual

symptoms varies among patients MSA is a progressive

disease, and symptoms worsen over time

Parkinsonism is the initial symptom in almost half ofall patients The classic symptoms of Parkinson’s disease

(PD)—tremor, stiffness or rigidity, and slowed

move-ments—are seen in MSA, although tremor is not as mon, and is jerkier than the tremor of PD

com-Cerebellar symptoms are the initial feature in veryfew MSA patients, but occur in about half of patients atsome point during the disease The cerebellum is an im-

portant center for coordination, and degeneration of thecerebellum in MSA leads to loss of balance, incoordina-tion in the limbs, and loss of smooth eye movements Aperson with cerebellar dysfunction in MSA typicallywalks with a wide stance to improve stability, and maylose the hand-eye coordination that makes so many simpleactivities possible

Autonomic symptoms refer to those involving the tonomic nervous system The autonomic nervous systemcontrols a variety of “automatic” body functions, includ-ing blood pressure, heart rate, sweating, and bladder func-tion Autonomic symptoms are the initial complaint in half

au-or mau-ore of all MSA patients The most common initialproblem is urinary dysfunction in women, and erectiledysfunction in men Urinary dysfunction may be inconti-nence, or inability to void the bladder Other autonomicsymptoms include lack of sweating, constipation, andfecal incontinence

Orthostatic hypotension is a common autonomicsymptom It refers to a significant drop in blood pressureshortly after standing It can cause dizziness, lighthead-

edness, fainting, weakness, fatigue, yawning, slurred

speech,headache, neck ache, cognitive impairment, and

eas-which is much more common Autonomic disturbance

also occurs in PD, but is much more pronounced in MSA

MSA is the more likely diagnostic choice when disease

progression is rapid, and when the patient responds mildly

or poorly to levodopa, the mainstay of PD treatment Some

centers use electromyography of the anal sphincter (the

muscles surrounding the anus) in order to confirm the

di-agnosis of MSA Abnormal results indicate MSA rather

than PD, although this method is not universally

The treatment team includes the neurologist,

possi-bly a movement disorders specialist, a urologist, and a

dopamine agonists Unfortunately, these are rarely as

ef-fective in MSA as they are in PD, although about one-third

of patients have at least a moderate response In the best

case, treatment relieves stiffness, tremor and slowed

move-ments, allowing increased activities of daily living

Orthostatic hypotension is treated with medications toincrease retention of fluids (fludrocortisone), compressive

stockings to keep blood from pooling in the legs,

increas-ing fluids, and increasincreas-ing salt intake Midodrine, a drug

that helps maintain blood pressure is often prescribed

A urologist may be needed to define the type of nary dysfunction the patient has, and to manage treatment

uri-A bedside commode or condom catheter may be helpful

for urge incontinence, or inability to hold urine once the

urge to urinate occurs If incomplete voiding is the

prob-lem, intermittent catheterization may be needed Detrusor

hyperreflexia, in which the bladder muscle undergoes

spasms, may be treated with drugs to reduce these spasms

Male erectile dysfunction may be treated with nafil or other medications

silde-Anhidrosis, or lack of sweating, can be dangerous in

an active patient, because of the risk of overheating.Awareness of the problem and avoidance of prolonged ex- ercise are helpful.

Gait ataxia may require a mobility aid, such as a

cane, walker, or eventually a wheelchair

Speech and swallowing problems are dealt with by aspeech/language pathologist, who may work with the pa-tient to develop swallowing strategies, and instruct in theuse of assistive communication devices Sleep apnea may

be treated with continuous positive airway pressure lation

venti-Clinical trials Clinical trials for MSA are usually directed toward

better diagnosis, or symptomatic treatment Until searchers develop a better understanding of the causes ofthe disease, little progress can be expected in development

re-of treatments to slow its progression

Prognosis

The average survival after diagnosis is 9-10 years.Death usually occurs from pneumonia or suddenly frominsufficient respiration, due to degeneration of the respi-ratory centers in the brain

Special concerns Resources

move-Muscular d

y also affected in some forms of MD, and a few forms

in-volve other organs as well The major forms of muscular

dystrophy include myotonic, Duchenne, Becker,

limb-gir-dle, facioscapulohumeral, congenital, oculopharyngeal,

distal, Emery-Dreifuss and Fukuyama muscular dystrophy

Description

The commonest form of these inherited disorders isthe Duchenne muscular dystrophy (DMD) The disorder

was originally described in the mid-nineteenth century by

the English physician Edward Meryon At a meeting of the

Royal Medical and Chirurgical Society in 1851, and later

published in the transactions of the society, he described

in detail the clinical presentation of Duchenne muscular

dystrophy, beginning in early childhood with progressive

muscle wasting and weakness and leading to death in late

adolescence Furthermore, his detailed histological studies

led him to conclude that the muscle membrane or

sar-colemma was broken down and destroyed

Duchenne muscular dystrophy will usually producesymptoms between the ages of three and seven in young

boys It begins with a weakness in the pelvic area first and

then progresses to the shoulder muscles As the disorder

escalates, the muscles enlarge although the muscle tissue

is weak The heart muscle will also enlarge, creating

prob-lems with the heartbeat that can be detected on an

elec-trocardiogram In most cases, the affected child has a

waddling walk, often falls, has difficulty rising from a

sit-ting position, has a difficult time climbing stairs, is unable

to fully extend the arms and legs, and may develop

scol-iosis (an abnormally curved spine) In most cases, children

with DMD are confined to a wheel chair between the ages

of ten and twelve

Most people with Becker muscular dystrophy (BMD)first experience difficulties between the ages of five and

fifteen years, although onset in the third or fourth decade

or even later can occur By definition, patients with BMD

are able to walk beyond age fifteen, while patients with

DMD are typically in a wheelchair by the age of twelve

Patients with BMD have a reduced life expectancy, but

most survive into the fourth or fifth decade Mental

re-tardation may occur in BMD, but it is not as common as

in DMD Cardiac (heart muscle) involvement occurs in

BMD and may result in heart failure

Myotonic muscular dystrophy (MMD) affects themuscles in the hands and feet Limb-girdle muscular dys-

trophy (LGMD) begins late in childhood affecting mainly

the muscles of the shoulders and hips

Facioscapulo-humeral muscular dystrophy (FSHD) affects only the

muscles of the upper arms, face and shoulder girdle

Lan-douzy-Dejerine muscular dystrophy (LDMD), which is

transmitted by an autosomal dominant gene, affects the

face, shoulder and lower leg muscles

Other disorders related to muscular dystrophy includeSteinert’s disease, Thomsen’s disease, and Pompe’s dis-ease Steinert’s disease affects both males and females,causing the muscles to be unable to relax after contracting,while Thomsen’s disease causes a stiffness of the legs,hands and eyelids Pompe’s disease, which is a glycogenstorage disease, affects the liver, heart, nerves and muscles

Demographics

United States

The incidence of muscular dystrophy varies, ing on the specific type Duchenne muscular dystrophy isthe most common condition It is inherited on the X chro-mosome, primarily affects boys, and is the most severetype of the disease Although women with the defectivegene are carriers, they usually show no symptoms DMDhas an inheritance pattern of 1 case per 3,500 live malebirths, and one-third of cases are due to spontaneous newmutations

depend-Becker muscular dystrophy is the second most mon form, with an incidence of 1 case per 30,000 livemale births Like DMD, BMD is linked to the X chromo-some Other types of MD are rare Limb-girdle musculardystrophy includes several different illnesses, which can

com-be inherited by both males and females, as can cioscapulohumeral muscular dystrophy

fa-International

The incidence of muscular dystrophies internationally

is similar to that of the United States, however some typesare especially frequent in certain populations and are rareelsewhere For example, autosomal dominant distal mus-cular dystrophy occurs more often in Scandinavia thanelsewhere, Fukuyama muscular dystrophy in Japan, ocu-lopharyngeal muscular dystrophy in French Canada, andseveral autosomal recessive LGMD in communities inBrazil, North America, and the Middle East

Causes and symptoms

All types of muscular dystrophy are inherited Theyare caused by a defect in one or more of the genes thatcontrol muscle structure and function Some types are in-herited as a dominant gene abnormality, while others areinherited as a recessive gene abnormality or an X-linkedrecessive gene abnormality In an X-linked recessive geneabnormality, the gene is on the X chromosome, one of thepair of chromosomes that determine a person’s sex.Both DMD and BMD are inherited X-linked recessivediseases affecting primarily skeletal muscle and the my-ocardium (heart muscle) Dystrophin, a large protein thatstabilizes the plasma membrane during muscle contrac-tions, is absent in DMD and reduced in BMD This results

Muscular d

Jerry Lewis, talking with Sarah Schwegel, MDA National Goodwill Ambassador, during the Muscular Dystrophy Association

Labor Day Telethon (Reproduced by permission of the Muscular Dystrophy Association.)

in an unstable muscle cell membrane and impaired

func-tion in the cell Muscle fibers continually deteriorate and

regenerate until the capacity for repair is no longer

suffi-cient Muscle fiber tissue is eventually replaced by fat and

connective tissue The abnormal gene for DMD and BMD

is on the short arm of the X chromosome at position Xp21

Two types of MMD are well recognized: ital (NC-MMD, not present at birth) and congenital (C-

noncongen-MMD, present at birth) In noncongen-MMD, a DNA sequence within

the gene on chromosome 19q 13.3, is repeated many

times, leading to an enlarged, unstable area of the

chro-mosome Called a triplet repeat mutation, the flawed gene

grows by sudden leaps when transmitted from generation

to generation, causing the disease to occur at a younger

age and in a more severe form (a phenomenon called

an-ticipation) C-MMD patients have been shown to have

substantially more repeats than those found in NC-MMD

patients

In FSHD, the abnormal gene is known to be near theend of chromosome 4 Exact DNA testing for diagnosticpurposes is not yet available except in some cases, a de-tailed genetic analysis of a particular family can be ac-complished

Genetic studies with LGMD have identified one formlinked to chromosome 15q, another form to chromosome2p, and two more severe forms to 13ql2 and 17ql2-q21.Symptoms can first appear during early childhood orlate in adult life, depending on the type of muscular dys-trophy

• Duchenne muscular dystrophy—Symptoms usuallybegin between ages two and four Because of a progres-sive weakening of leg muscles, the child falls frequentlyand has difficulty getting up from the ground The childalso has trouble walking or running normally By age 12,most patients are unable to walk and are limited to a

Muscular d

y wheelchair As the illness progresses, there also is an

ab-normal curvature of the spine

• Becker muscular dystrophy—Symptoms are similar to

those of DMD, but they are milder and begin later, ally between ages five and fifteen

usu-• Myotonic muscular dystrophy—Muscle myotonia may

develop soon after birth or begin as late as early hood, and especially affects the hands, wrists and tongue

adult-There also is wasting and weakening of facial muscles,neck muscles, and muscles of the wrists, fingers and an-kles Involvement of the tongue and throat musclescauses speech problems and difficulty swallowing If thediaphragm and chest muscle also are involved, there may

be breathing problems

• Limb-girdle muscular dystrophy—Symptoms begin in

late childhood or early adulthood They include gressive muscle weakness in the shoulders and hips, to-gether with breathing problems (if the diaphragm isinvolved) If illness also affects the heart muscle, theremay be heart failure or abnormal heart rhythms

pro-• Facioscapulohumeral muscular dystrophy—Symptoms

may begin during infancy, late childhood, or early hood Usually, the first sign is facial weakness with dif-ficulty smiling, whistling and closing the eyes Later,there is difficulty raising the arms or flexing the wristsand/or ankles

adult-Diagnosis

The diagnosis of muscular dystrophy is made with aphysical examination and diagnostic testing by the child’s

physician During the examination, the child’s physician

obtains a complete prenatal and birth history and asks if

other family members are known to have MD In addition

to a clinical history and a physical exam, others exams

may be suggested:

• Serum creatine kinase—Measurement of serum (a blood

component) concentration of creatine kinase is a simpleand inexpensive diagnostic test for severe forms of dys-trophy known to be associated with high concentrations

of creatine in the blood In DMD, serum creatine kinasevalues are raised from birth, and testing in newborns forearly diagnosis could reduce the possibility of further af-fected boys in a family and improve medical assistancebefore the onset of symptoms

• Electromyography—This test is important in the

estab-lishment of the myopathic (muscle disease not caused bynerve dysfunction) nature of the disease and for the ex-clusion of neurogenic (from the nerves) causes of weak-ness, including peripheral nerve disorders Because

electromyography is an invasive technique involving a

needle stick, it is becoming less favored in the gation of children, but it still has an important role in thediagnosis of adult disease

investi-• Muscle histology—The one unifying feature of the trophies is their similar muscle histological (in the tis-sues) findings, such as variation in muscle fiber size,muscle fiber death, invasion by macrophages (a versatileimmune cell), and ultimately, replacement by fat andconnective tissue This picture is aggravated in the moresevere forms of dystrophy, such as Duchenne type How-ever, in FSHD and LGMD, inflammatory changes in tis-sues are often the main features

dys-• Immunohistochemistry and mutation analysis—In somemuscular dystrophies, certain proteins are deficient inmuscle tissue Immunohistochemistry involves methods

of detecting the presence of these specific proteins inmuscle cells or tissues A diagnosis can be made whenthese protein deficiencies are identified Analysis ofgenetic mutations associated with muscular dystrophies

is also important for genetic counseling and prenataldiagnosis

Treatment team

There are many professionals available to help thechild with muscular dystrophy, depending on the patient’sneeds These include physicians, orthopedic surgeons(bone specialists), physical therapists, orthotists (special-ists on equipment to maintain posture and mobility), oc-cupational therapists, dietitians, nurses,social workers,

psychologists, teachers, religious advisers, staff from theMuscular Dystrophy Association, parents, and other per-sons with MD

Physical therapy involves a program of stretching ercises to maintain muscle length and the flexibility ofjoints Physical therapists also work with orthotists Nightsplints, calipers, swivel walkers, and braces are some ofthe aids employed Physical therapists are the main pro-fessionals involved in teaching parents the appropriate ex-ercises and in making sure that any mobility aids arecomfortable Both physical therapy and hydrotherapy(water therapy) contribute significantly to mobility andrespiratory function

Specific treatment for muscular dystrophy is mined by the child’s physician based on age, overall

caused by a dominant mutant gene that can be

in-herited by either parent

Autosomal recessive disorder A genetic disorder

that is inherited from parents that are both carriers,

but do not have the disorder Parents with an

af-fected recessive gene have a 25% chance of

pass-ing on the disorder to their offsprpass-ing with each

pregnancy

Dystrophin A large protein that stabilizes the

plasma membrane of a muscle cell during muscle

contractions Dystrophin is absent or reduced in the

most common forms of muscular dystrophy

Electromyography A test used to detect nerve

function It measures the electrical activity

gener-ated by muscles

Immunohistochemistry A method of detecting

the presence of specific proteins in cells or tissues

Macrophage A large, versatile immune cell that

acts as a scavenger, engulfing dead cells, foreign

substances, and other debris

Mutation A permanent, heritable change in a

gene or chromosome structure

Myopathy Refers to a disorder of the muscle,

usu-ally associated with weakness

Myotonia Abnormally long muscular contractions.

health, medical history, extent of the condition, type of

condition, child’s tolerance for specific medications,

pro-cedures or therapies

Drug therapies

In children with Duchenne muscular dystrophy, costeroids (such as prednisone) may be prescribed to tem-

corti-porarily delay progression of their illness; however, some

patients cannot tolerate this medication because of side

ef-fects Powerful medications that suppress the immune

sys-tem have been reported to help some patients, but their use

is controversial In patients with MMD, myotonia

(abnor-mally long muscular contractions) may be treated with

medications such ascarbamazepine or phenytoin.

Gene therapy

With advances in molecular biology techniques, other method of treatment currently under intense investi-

an-gation is somaticgene therapy The idea is to introduce

healthy immature cells into affected muscles, which wouldfuse and stimulate production of enough dystrophin to re-verse the degeneration already taking place Although thishas been achieved successfully in mice, the benefit may nottranslate into humans The mice cannot demonstrate mus-cle strength, and the laboratory-raised mice were not able

to mount a rejection response that may occur in humans

Other therapies

The orthopedic problems in children with MD lead toprogressive weakness with walking difficulties, soft-tissuecontractures, and spinal deformities The role of the or-thopedic surgeon is to correct deformities and help main-tain the child’s ambulatory status for as long as possible.The modalities available to obtain these goals include:functional testing; physical therapy; use of orthoses (spe-cialized aids); fracture management; soft tissue, bone, andspinal surgeries; use of a wheelchair when indicated; andgenetic and/or psychological testing

Recovery and rehabilitation

To date, there is no known treatment, medicine, orsurgery that will cure MD, or stop the muscles from weak-ening The goal of treatment is to prevent deformity andallow the child to function as independently as possible athome and in the community

Physical therapy

In general, patients are given supportive care, togetherwith leg braces and physical therapy to maximize theirability to function in daily life Stretching limbs to avoidtightened tendons and muscles is particularly important.When tightness of tendons develops (called contractures),surgery can be performed When chest muscles are in-volved, respiratory therapy may be used to delay the onset

of breathing problems In addition, people with MD aregiven age-appropriate dietary therapy to help them avoidobesity Obesity is especially harmful to patients with MDbecause it places additional strain on their already weakmuscles Unfortunately, many MD patients are at a highrisk of obesity because their limited physical activity pre-vents them from exercising

Wheelchair prescription

If the person with MD becomes nonambulatory,wheelchair mobility is essential The wheelchair shouldcomplement the patient’s lifestyle, providing comfort,safety, and functionality Special attention should begiven to the frame, seat, backrest, front rigging, rearwheels, and casters because of the functional weaknessand contractures in the upper and lower extremities of pa-tients with limb-girdle dystrophy An accessible home