HARR|SON’S
`PRINCIPLES OF
`
`Internal
`Medicine
`
`Editors
`
`DENNIS L. KASPER, MD
`
`William Ellery Channing Professor of Medicine.
`Professor of Microbiology and Molecular Genetics.
`Harvard Medical School: Director. Charming
`Laboratory. Department of Medicine. Brigham and
`Women‘s Hospital. Boston
`
`EUGENE BRAUNWALD, MD
`
`Distinguished Hersey Professor of Medicine.
`Harvard Medical School: Chairman. TIMI Study Group.
`Brigham and Women's Hospital. Boston
`
`MD
`Chief. Laboratory of Immunoregulation; Director.
`National institute of Allergy and infectious Diseases.
`National Institutes of Health. Bethesda
`
`MD
`L‘
`Scientific Director. National Institute on Aging.
`National Institutes of Health.
`Bethesda and Baltimore
`
`STEPHEN L. HAUSER, MD
`Robert A. Fishman Distinguished Professor and Chairman.
`Department oi" NeL:rolo_i_zy.
`University of Calitbrnia San Francisco. San Francisco
`
`J. LARRY JAMESON, MD, PHD
`Irving 3. Cutter Professor and Chaimtan.
`Department of Medicine.
`Northwestern University Feinberg School of Medicine:
`Physiciazvin-Chief. Northwestern
`Memorial Hospital. Chicago
`
`M'
`exico
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`C't
`iy
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`New York
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`y gyahtfgiltinfixhlblt
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`Ii-.irrisun‘s
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`I’RI':\'(_'II’[.I-‘.5 U!“ l\'l"l'7.R.\‘_-\I. !VIl1lI)I(.‘lNI<".
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`2005. Zlllll. I998. I994. I991. I987. I983. I980. I977, 1974. 1970. I966. I962. I958 by The
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`tM[‘GI'L!\\‘-['{I'II CtJHI[_7('Jiiit".\'. liar. All rights reserved. Printed in the United States of America. Except as per-
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`ISBN 0-07439140-I (Set)
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`Libby Pisacreta; cover design by Janice Bielawa. Medical illustrator: Jay McEIroy. MAMS.
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`Library of Congress Cataloging-in-Publication Data
`
`Harrison's principles ofinternal medicinea l6th ed./editors. Dennis L. Kasper .
`Includes bibliographical references and index.
`ISBN t)-f)7'il'39|4('J—l (set)/ISBN 0—07-13914]-X (v. lt—lSBN U-O7Vl39l42—8 (v. 2)~ISBN 0-07-
`l—IU.'-35-7 (combo)
`
`[et al.}.
`
`p. cm.
`
`.
`
`.
`
`I. Internal medicine. I. Title: Principles of internal medicine. ll. Kasper. Dennis L. Ill. Harrison.
`Tinsiey Randolph.
`l9(lH— Principles of internal medicine.
`IDNLM: 1. Internal Medicine. W8 I15 H332 200:3]
`RC46,H333 2005
`6 I 6—de2I
`
`200404493 I
`
`Page 2 of 13
`
`Page 2 of 13
`
`

`
`‘ifllifil lli.l'lljJii‘ii1
`IN A el al: Primary brain tumors in adults. Lancet 36l:323. 2003
`
`'
`,
`I M El at Temozolomide as an akemative to irradiation for eideriy
`in Nil-iits with newly diagnosed malignant gliomas Cancer 972262 2003
`, pa
`.
`.
`.
`.
`
`2451
`35! Multiple Sclerosis anti Other Demgelinatiiig Diseases
`ZHU Y, PARADA LF: The molecular and genetic basis ofneurological tumors.
`Na‘ REV Cancer 2515' 2002
`
`iiiiiimr St'lER{iSlS aiio OTHER DEMYELINATING DISEASES
`
`Stephen L Huuser, Douglas 5. Gaadiii
`
`3.?
`
` .
`
`yclinating disorders are characterized by inflammation and se1ec-
`"destruction of central nervous system (CNS) myelin. The periph-
`ncrvous system (PNS) is spared, and most patients have no
`c1lL‘L' of an associated systemic illness.
`
`'
`
`;
`LTIPLF '3Cl_lEilll‘;l1-
`-i triple sclerosis (MS) is characterized by a triad of inflammation.
`.
`.
`.
`.
`.
`"_..ycliiiation, and gliosis (scarring); the course can be relapsmg—re— A
`fling or progressive. Lesions of MS are typically disseminated in
`'7‘. and location. MS affects -350.000 Americans and l.l million
`‘vidtuils worldwide. In westem societies. MS is second only to
`" ma as a cause of neurologic disability in early to middle adulthood.
`"ii. ifesiations of MS vary from a benign illness to a rapidly evolving
`’- incapacitating disease requiring profound life-style adjustments.
`
`Sallaiory "SW9 i|'|'|l'-lU|SE
`
`S 71 —\—
`2
`/- Y C
`
`
`
`Na" channels
`
`Node of Flanvier
`
` 0GEllES|5 A Anatomy These lesions (plaques) vary in size froml
`
`Na" channels
`
`ii mm to several centimeters. Acute MS lesions are characterized
`B
`iberivenular cuffing with inflammatory mononuclear cells. predom-
`Nerve conduction in muelinated and derngelinateo axons. A. Saltatorg
`FIGURE 359-1
`in ily T cells and macrophages, which also infiltrate the surrounding
`nerve conduction in myeiinated axons occurs with the nerve impulse jumping from one
`--‘E Mme, A, sites of inflammation [he bl0od_bral-n harder (BBB)
`node of Ranvier to the next. Sodium channels are concentrated at
`the nodes where
`.5
`.
`.
`.
`.
`axonal depolarization occurs. 8. Following iiemuelination,
`the sodium channels are re-
`Srupled but‘ unhke vasculms‘ the vessel wall 1Spre5eWed' Inmate
`distributed along the axon,
`tnerelig supporting continuous propagation of the nerve
`fi“ 13"” Of CaSe5- mYel""'-lpecific a”[°3mib°di"*5 Promote demyelin‘
`
`_,
`and stimulate macrophages and microglial cells (bone marrow— anion pmmiai in this regim
`“ved CNS phagocytes) that scavenge the myelin debris. As lesions
`lve. astrocytes proliferate (gliosis). Surviving oligodendrocytes or
`
`that differentiate from precursor cells may partially remyelinate
`vary from hour to hour or in association with fever or exercise. Con-
`-surviving naked axons, producing so-called shadow plaques. Ul-
`duction slowing occurs when the demyelinated segments support only
`ruciural studies of MS lesions suggest that fundamentally different
`(slow) continuous nerve impulse propagation.
`Epidemiology MS is approximately twice as common in women as in
`rlying pathologies may exist in different patients. Heterogeneity
`been observed in terms of: (1) whether the inflammatory cell in- men. The age. of onset is typically between 20 and 40 years (slightly
`_ii: is associated with deposition ofantibody and activation ofcom-
`later in men than in women). Rarely. it can begin as early as 2 years
`em. and (2) whether the target of the irnmunopathologic process
`of age or as late as the eighth decade.
`iii myelin sheath itself or the cell body of the oligodendrocyte.
`The highest known prevalence for MS (250 per 100.000) occurs in
`ougli sparing of axons is typical of MS. partial or total axonal
`the Orkney islands. located north of Scotland, and similarly high rates
`_ ction can also occur. Indirect evidence suggests that axonal loss
`are found throughout northern Europe. the northern United States, and
`' ujor cause of irreversible neurologic disability in MS.
`Canada. By contrast. the prevalence is low in Japan (2 per 100,000).
`lagg Nerve conduction in myelinated axons occurs in a saltatory
`in other parts of Asia, in equatorial Africa. and in the Middle East. In
`__~ er. with the nerve impulse jumping from one node of Ranvier to
`general. prevalence increases with increasing distance from the equa-
`jest without depolarization of the axonal membrane underlying
`tor, although certain exceptions are notable. Thus. the incidence of MS
`ft yelin sheath between nodes (Fig. 359-1). This produces consid-
`in the Eskimo population of Alaska is rare compared to the incidence
`ly faster conduction velocities (~70 in/s) than the slow velocities
`in Caucasians living at similar latitudes. Similarly, native South Af-
`3; 5) produced by continuous propagation in unmyelinated nerves.
`ricans have a markedly lower prevalence compared to South Africans
`ticiion block occurs when the nerve impulse is unable to traverse
`of European descent who live in the same geographic area. However,
`tlcmyelinated segment. This can happen when the resting axon
`distinctive migration patterns of certain populations may artifactually
`__brane becomes hyperpolarized due to the exposure of voltage-
`suggest a relationship between MS and climate. Thus. when Scandari-
`. dent potassium channels that are normally buried underneath the
`avians migrated to the United States or when the Scots migrated to
`
`sheath. A temporary conduction block often follows a demy-
`New Zealand, they tended to migrate preferentially to places (e.g., the
`._
`5; event before the sodium channels (originally concentrated at
`northern United States or southern New Zealand) with similar climates
`30d!‘-S) have had a chance to redistribute themselves along the
`to their native lands. Such considerations point to potential genetic
`-‘ axon (Fig. 359-I ). This redistribution ultimately allows the con-
`mechanisms (see below) rather than to an influence of temperate cli-
`mate per se.
`_:.'_. propagation of nerve action potentials through the demyelin-
`'§€gment but, before this happens, the leakage currents are too
`CHANGES IN INCIDENCE/PREVALENEE Studies from the United States.Europe,
`-for the nerve impulse to jump the intemode distance and con- Australia. and the Middle East suggest that the prevalence of MS
`fails. On occasion, conduction block is incomplete, affecting. may be increasing. although improved methods of diagnosis may ac-
`.n_1ple. high- but not low-frequency valleys ofimpulses. Variable
`count for the apparent change. Other reports suggest that individuals
`l_l.33lD[1 block can occur with raised body temperature ormetabolic who move from an area of high prevalence to one of low prevalence
`lions and may explain clinical fluctuations (typical of MS) that
`(or vice versa) before the age of 15 years adopt the risk ofMS in their
`
`Page 3 of 13
`
`

`
`
`
`EYTGKJNES (Chap. 295) The proinflarnmatory THI cym '
`interleukin (LL) 2, l.'L1I'l'10l' necrosis factor (TNF) or, and inte"
`y are thought to be central to MS pathogenesis and some,
`at and [FN-'y) may directly injure oligodendrocytes or the '
`branes. Nevertheless, the notion of an isolated THI imb '-
`MS is probably simplistic. The presence of autoantibodigg
`gests that regulatory TH2 cytokines (including IL-4, -5‘
`also play a pathogenic role. Moreover,T,,1-based tlrerapig:
`
`proved to be unhelpful or. in the case of certain TNF-I
`harmful to patients.
`-
`
`
`
`TRlEE£R5 Magnetic resonance imaging (MRI) has demons
`of disease activity 7 to 10 times more frequently than ‘ fir
`apparent. This finding indicates that there is a large rese}
`clinical disease activity in MS, especially during the ear!
`the disease. The triggers causing these bursts are unkno '
`the fact that patients may experience relapses after non
`respiratory infections suggests that either molecular mirni
`viruses and myelin antigens or viral superantigens activa
`genie T cells may play a role in MS pathogenesis. (Chap.-2
`Microbiology As noted above, epiderniologic evidence .
`role of an environmental exposure in MS. MS risk also come.
`
`sequelae more frequently when the age of initial infection’
`The best studied experimental model of virus-induct-ti de
`disease is infection with Theiler virus. a murine coronav'
`measles, which produces a chronic oligodendrocyte inf _
`multifocal perivascular lymphocytic infiltration and tlern '
`closely resembling lesions of MS.
`High antibody titers against many viruses have been
`serum and CSF of MS patients, including measles. herpes
`varicella, rubella. Epstein-Barr. and influenza C and some
`enza strains. Numerous viruses and bacteria (or their ge
`quences) have been recovered from MS tissues and ii _
`recently human herpes virus type 6 (HHV-6) anti Clrlanry
`rrtortiae have been implicated, although a causal role for any _
`agent in MS remains unproven.
`
`
`
`ELINFCAL MANIFESTATIGNS The onset of MS may be abrupt Oflll
`Symptoms may be severe or seem so trivial that a pati
`seek medical attention for months or years. Indeed. at 2!
`individuals who were asymptomatic during life will be i0 ,
`pectedly. to have MS. In other cases an MRI scan obtain
`unrelated reason may show evidence of asymptomatic MS.
`of MS are extremely varied and depend upon the location
`within the CNS (Table 359- l ). Examination generally rCV63l
`of neurologic dysfunction. often in asymptomatic loculifllis
`ample. a patient may present with symptoms in one lee an
`both.
`
`
`
`l'ABlE 359-1
`
`initial Symptoms of M5
`
`Symptom
`
`Percent of Cases
`
`Symptom
`
`Sensory loss
`Optic neuritis
`Weakness
`Paresthesias
`Diplopiu
`Ataxia
`Vertigo
`Paroxysmal attacks
`Bladder
`
`37
`36
`35
`24
`15
`1 I
`6
`4
`4
`
`Lhcrmitte
`Pain
`Dementia
`Visual loss
`Facial palsy
`Impotence
`Myoitymla
`Epilepsy
`Falling
`
`Source: After WE Matthews et al. Mt:At'pr'rre's Multiple Sclamsrlr. NL‘“‘ Y°‘k'
`Livingstone. 1991.
`
`
`
`2462
`
`Part XV Neurulagit Disorders
`
`new environment. whereas if they move after this age. they retain the
`risk of their native land. The reliability of these observations is un-
`certain, although, if correct. they would suggest an environmental fac-
`tor in the pathogenesis of MS.
`
`REPDRTED cwsrtrrs Clusters of MS cases are occasionally reported. Of-
`ten these apparent epidemics cannot be distinguished easily from
`chance occurrences. although some reports (e.g., the clustering of MS
`cases in the Faeroe Islands after British occupation during World War
`II) are more convincing than others. Such clustering, however, seems
`to be rare.
`
`The Relationship of M5 tn Trauma and Stress The existing evidence does
`not support any association of trauma with either MS onset or exac-
`erbation. Similarly. a relationship between stress and either onset or
`exacerbation of MS has not been established. although this area is not
`easily studied because of difficulties in quantifying stress.
`
`
`GENETIC [Dll5lDERATl0N5 A genetic susceptibility to MS exists.
`as evidenced by the following observations:
`1. The prevalence of MS differs among ethnic groups residing in the
`same environment.
`
`2.
`
`First-. second-. and third-degree relatives of MS patients are at
`increased risk for the disease. Siblings of affected individuals have
`a lifetime risk of 2 to 5%. whereas the risk to parents or children
`of affected individuals is somewhat lower.
`3. Twin studies demonstrate concordance rates of 25 to 30% in
`monozygotic twins compared to only 2 to 5% in dizygotic twins
`(similar to the risk in nontwin siblings).
`The inheritance of MS cannot be explained by a simple genetic
`model. Susceptibility is probably polygenic. with each gene contrib-
`uting a relatively small amount to the overall risk. It is also likely that
`genetic heterogeneity (different susceptibilities among individuals)
`also exists. The major histocompatibility complex (MHC) on chro-
`mosome 6p2l (encoding proteins involved in presenting peptide an-
`tigens to T cells) is the most
`important MS susceptibility region
`identified to date. MS susceptibility is associated with the class ll
`region of the MHC. specifically with the DR2 (DRBl*l50l) allele
`and its corresponding haplotype. Other genetic regions implicated in
`MS susceptibility are located on chromosomal regions l9q35 and
`l7ql3.
`
`
`Immunology An autoimmune cause for MS is supported by the labo-
`ratory model of experimental allergic encephalomyelitis (EAE) and by
`studies of the immune system in MS patients.
`
`AUTUREACTWE TLYMPHGEYTES Myelin basic protein (MBP) is an important
`T cell antigen in EAE and probably also in human MS. Activated
`MBP-reactive T cells are often found in the blood or cerebrospinal
`fluid (CSF) of MS patients and. occasionally also.
`in MS lesions.
`Moreover. DR2 may influence the autoimmune response because it
`binds with high affinity to a fragment of MBP (spanning amino acids
`89 to 96), stimulating T cell responses to this self-protein.
`
`AUIUANIIBODIES Autoantibodies, directed against myelin antigens such
`as myelin oligoderrdrocyte glycoprotein (MOG), probably act in con-
`cert with a pathogenic T cell response to cause the demyelinating le-
`sions in many patients. Recent evidence suggests that the presence of
`anti MOG antibodies in the serum of patients with a clinically isolated
`syndrome (CIS) is highly predictive of the development of MS in the
`future. Also. evidence of an abnormal humoral immune response is
`present in the CSF of MS patients. Membrane attack complexes (from
`complement-mediated antibody damage) can be detected in CSF. and
`elevated CSF immunoglobulin (synthesized locally) is characteristic
`of MS. Oligoclonal antibody (derived from expansion of a selected
`group of plasma cells) is present in most cases. Oligoclonal immu-
`noglobulin is also detected in other chronic inflammatory conditions.
`Page 4 of 13
`
`Page 4 of 13
`
`

`
`allies: ofthe limbs may manifest as loss of strength or dexterity.
`_ or a disturbance of gait. Exercise—induced weakness is a char-
`"stic symptom of MS. The weakness is of the upper motor neuron
`(Chap. 20) and is frequently accompanied by other pyramidal
`ugh as spasticity. hyperreflexia and Babinski signs. Occasion-
`; tendon reflex may be lost (simulating a lower motor neuron
`' } ‘;|'a_rt MS lesion disrupts the afferent reflex fibers in the spinal
`
`..
`
`gsririty (Chap. 21) is often associated with spontaneous and
`em-induced muscle spasms. More than 30% of MS patients
`udEI‘3.l.6 to severe spasticity, especially in the legs. It is often
`, panied by painful spasms and can interfere with a patient's abil-
`ambulate or work or with self-care. Occasionally, spasticity may
`‘dc nonvolitional support for the body weight during ambulation.
`353 cases, treatment of spasticity may actually do more harm than
`
`359 Multiple Sclerasis and Either Demuelinatinq Diseases
`
`2463
`
`bladder emptying. Detrusor sphincter dyssyncrgia. due to loss of syn-
`chronization between detrusor and sphincter muscles, causes difficulty
`in initiating and/or stopping the urinary stream. thereby producing hes-
`itancy. It can also lead to urinary retention, large postvoid residual
`volumes. overflow incontinence, and recurrent infection.
`Consripation occurs in >30% of patients. Fecal urgency or bowel
`incontinence is less common (15%) but can be socially debilitating.
`Cognitive dysfunction can include memory loss, impaired attention,
`difficulties in problem-solving, slowed infonnation processing, and
`problems shifting between cognitive tasks. Euphoria (elevated mood)
`was once thought to be characteristic of MS but is actually uncommon,
`occurring in <20% of patients. Cognitive dysfunction sufficient to
`impair activities of daily living also occurs but is rare.
`Depression. experienced by 50 to 60% of patients. can be reactive,
`endogenous, or part of the illness itself and can contribute to fatigue.
`Suicide in MS patients is 75-fold more common than in age-matched
`controls.
`
`Farigue is experienced by 90% of patients and is moderate or severe
`in half. Symptoms include generalized motor weakness, ljrnited ability
`to concentrate, extreme lassitude. loss of energy. decreased endurance.
`and an overwhelming sense of exhaustion that requires the patient to
`rest or fall asleep. Fatigue (either alone or with other symptoms) is the
`most common reason for work-related disability in MS. Fatigue can
`be exacerbated by elevated temperatures, by depression. by expending
`exceptional effort to accomplish basic activities of daily living. or by
`sleep disturbances (e.g.. from frequent nocturnal awakenings to uri-
`nate). MS-related fatigue may be maximum during mid-aftemoon or
`continuous throughout the day. and it is often difficult to treat.
`Sexual dysfunction is common in MS. Men report impotence, less
`desire. impaired genital sensation. impai.red ejaculation. and inability
`to achievelmaintain an erection. Women report genital numbness. di-
`minished orgasmic responsc. decreased libido. unpleasant sensations
`during intercourse, and diminished vaginal lubrication. Adduclor spas-
`ticity (in women) can also interfere with intercourse. and urinary in-
`continence (in either men or women) can be problematic.
`Facial weakness due to a lesion in the intraparenchymal pathway
`of the seventh cranial nerve may resemble idiopathic Bell's palsy.
`However, unlike Bell‘s palsy. facial weakness in MS is generally not
`associated with ipsilateral loss of taste sensation or retroauricular pain
`(Chap. 355).
`Vertigo may appear suddenly and resemble acute labyrinthitis. A
`brainstem rather than end-organ origin is suggested by the presence of
`coexisting trigeminal or facial nerve involvement; vertical nystagmus;
`or nystagmus that has no latency to onset, no direction reversal, and
`doesn’t fatigue (Chap. 20). Hearing loss may also occur in MS but is
`uncommon.
`
`Ancillary Symptoms Hearsensitiviry refers to neurologic symptoms pro-
`duced by an elevation of the body's core temperature. For example,
`transient unilateral visual blurring or loss may occur during a hot
`shower or with physical exercise (Uhrnojfs symptom). It is common
`for MS symptoms to worsen transiently, sometimes dramatically, dur-
`ing febrile illnesses (see pseudoexacerbation, below). Such heat-re-
`lated symptoms probably result from transient conduction block (see
`above).
`
`Lhermirre"s symptom is the electric shock—like sensation (evoked
`by neck flexion or other movement) that radiates down the back into
`the legs. Rarely, it radiates into the arms. It is generally self-limited
`but may persist for years. Lherrnirte’s symptom can also occur with
`other disorders of the cervical spine (e.g.. cervical spondylosis).
`Paroxysmal symptoms are distinguished by their brief duration
`(30 s to 2 min), high frequency (5 to 40 episodes per day), lack of any
`alteration of consciousness or change in background electroencepha-
`logram during episodes, and a self-limited
`course (generally lasting
`weeks
`to months). They may be precipitated by hyperventilation or
`movement. These syndromes include Lherrnitte’s symptom; tonic con-
`
`
`
`_' pt.-1' neuritis (ON) generally presents as diminished visual acuity.
`less. or decreased color perception (desaturation) in the central
`‘ 0fvlslOl'l. These symptoms may be mild or may progress to severe
`'
`loss. Rarely, there is complete loss of light perception. Visual
`ems are generally monocular but may occur bilaterally. Perior-
`_pain (aggravated by eye movement) often precedes or accom-
`es the visual loss. An afferent pupillary defect (Chap. 25) may be
`*5, Funcluscopic examination may be normal or reveal optic disc
`jig (papillitis). Pallor of the optic disc (optic atrophy) commonly
`'ws ON. Uveitis is rare and should raise the possibility of alter-
`: ‘e diagnoses. -0N is discussed in detail‘ in Chap. 25.
`‘ usual blurring in MS may result from ON or diplopia. Visual
`" E: that resolves when either eye is covered is due to diplopia.
`iplapia may result from internuclear ophthalmoplegia (INO) or
`fpalsy of the sixth cranial nerve (rarely the third or fourth). An
`_ consists of impaired adduction of one eye due to a lesion in the
`tentl medial longitudinal fasciculus (Chap. 25). Prominent nys-
`'s often observed in the abducting eye, along with a small skew
`l0l'l. A bilateral INO is particularly suggestive of MS. Other com-
`aze disturbances in MS include: (I) a horizontal gaze palsy. (2)
`and a half” syndrome (horizontal gaze palsy plus an INO), and
`_
`ii uired pendular nystagmus.
`nsmjv symptoms are varied and include both paresthesias (e.g.,
`i g. prickling sensations, formications. “pins and needles," or
`hunting) and hypesthesia (e.g., reduced sensation, numbness
`cad" feeling). Unpleasant sensations (e.g., feelings that body
`re swollen. wet. raw, or tightly wrapped) are also common.
`ry impairment of the trunk and legs below a horizontal line on
`so (a sensory level) suggests that the spinal cord is the origin
`ensory disturbance. It is often accompanied by a bandlilte sen-
`-»
`':'»I of tightness around the torso. Pain is a common symptom of
`ixperienced by >50% of patients. Pain can occur anywhere on
`y and can change locations over time.
`axiu usually manifests as cerebellar tremors (Chap. 21). Ataxia
`so involve the head and trunk or the voice. producing a char-
`ic cerebellar dysarthria (scanning speech). The true extent of
`}
`ar involvement may be difficult to determine in an individual
`'
`because motor and sensory deficits can affect coordination and
`‘,
`-if ess may interfere with coordination resting.
`ladder and bowel dysfunction arise from different causes and fre-
`-‘._l)l different types of dysfunction coexist. During normal reflex
`l g. relaxation of the bladder sphincter (oz-adrenergic innervation)
`fl dinated with contraction of the detrusor muscle in the bladder
`jlllluscarinic cbolinergic innervation). Stoppage of the urinary
`is accomplished with a coordinated sphincter contraction and
`1’ relaxation. Bladder-stretch (during filling) activates this re-
`hich is inhibited by supraspinal (voluntary) input. Symptoms
`_der dysfunction are present in >90% of MS patients and, in a
`:dYsl'unction results in weekly or more frequent episodes of in-
`
`ffrttsor hyperrefiexia, due to impairment of suprasegmental in-
`.11. causes urinary frequency. urgency, nocturia, and uncontrolled
`
`Page 5 of 13
`
`

`
`sex distribution is more even, the disease begins later in lif
`Part XV Neurolugit Disorders
`2454
`age. ~40 years). and disability develops faster. Whether PP
`unusual phenotype ofthe same underlying illness as RRM3 or
`tractions of a limb, face, or trunk (tonic seizures); paroxysmal dysar-
`these are distinct illnesses is unknown.
`thriafataxia; paroxysmal sensory disturbances; and several other less
`4. Progressive/relapsing MS (PRMS) overlaps PPM5 mi‘
`well characterized syndromes. Paroxysmal symptoms probably result
`and accounts for ~5% of MS patients. Like patients with PPMS
`from spontaneous discharges, arising at the edges of demyelinatcd
`patients experience a steady deterioration in their condition W
`plaques, and spreading ephaptically to adjacent white matter tracts.
`ease onset. However, like SPMS patients. they experience occ
`Trigeminal neuralgia, hemifacial spasm, and glossophaiyngeal
`attacks superimposed upon their progressive course (Fig, 359- ‘
`neuralgia can occur when the demyelinating lesion involves the root
`early Stages of RPMS are indistinguishable from those of PP ’
`entry (or exit) zone of the fifth. seventh, and ninth cranial nerve, re-
`until the first clinical attack).
`"
`spectively. Trigeminal neuralgia (tic douloureux) is a very brief lan-
`DIAGHGSIS There is no dafimvtive diagnostic test for MS. D
`cinating facial pain often triggered by an afferent input from the face
`.
`.
`.
`.
`.
`.
`,
`or teeth. Most cases of trigeminal neuralgia are not MS-related. How-
`cmena for Chmcany defimte MS require “°°“".‘°“'*"'°" of.
`ever, the occurrence of atypical features (Chap. 355) such as the onset
`before age 50 years, bilateral symptoms. objective sensory loss. or more eplsudes of Symptoms and two or more “gm ‘hat "3
`.
`.
`.
`thology in anatomically noncontiguous white matter tracts of
`nonparoxysmal pain should raise concerns that a sym tomatic cause
`Such as MS is l_eSp0nSib]e_
`P
`(Table 359-2). Symptoms must last for >24 h and occur as
`Facial myokymia consists of either persistent rapid flickering con-
`episodes .thal aim separated by a month or more‘, At 1635} °n '
`tractions of the facial musculature (especially the lower portion of the
`two required slgns must be present. on neumloglc ex.a"."m“ .
`orbicularis oculus) or a contraction that slowly spreads across the face.
`Sccund may be documenied by Canal“ abiiomal paractinical w I
`It results from lesions of the corticobulbar tracts or brainstem course
`as MR] ‘if evoked. poieimals USPS)‘ In patmmi who “pen
`of the facial name.
`progression of disability for 2.6 months with
`lapses, documentation of intrathecal IgG and v
`DISEASE COURSE Four clinical types of MS have been described (Fig.
`used to support the diagi-;osi5_
`9-
`:
`35 1.2) Relapsing/remitting MS (RRMS) accounts for 85% of MS
`PIAENUSHF TESTS_. Magnet“ Resonant‘ maginfl MRI 1"” ""’°-
`cases at onset and is characterized by discrete attacks that generally
`‘zed the d_"_‘§n°515 and mflnagemel“ 0f M5 (F1E’.- 3'59-3); Chara _
`evolve over days to weeks (rarely over hours). Often, but not invari— abnomaililes are found m >95% of Patients,’ An Increase "1 V"
`ably, there is complete recovery over the ensuing weeks to months
`_pe’meab'my fmm_a_breakd°“’_" Ofthe BBB '5 detected by leak.
`(Fig. 359-2A). However, when ambulation is severely impaired during m"aVe"°”_5 gad°1m“.’m (Gd) mm the P3’e'?°hY"‘a- Such Ie
`an attack, approximately half will fail to improve. Between attacks,
`curs ea‘-1y_m the d°‘{°'°P"‘°“‘ of an MS [e§1°n_and Serve“ as 33-
`patienis are neurologically stable,
`marker of inflammation. Gd—erihancemerit persists for up to 3 m‘
`2. Secondary pmgremw MS (SPMS) always begins as RRMS
`and the residual MS plague remains visible indefinitely as a f V
`(Fig. 359-2B). At some point, however. the RRMS clinical course
`of “¥P°1f'““"““¥ (a,]eS1°") 0" 5Pm'ech° _(T2'we'ght'3d),a"d=p
`changes so that the patient experiences a steady deterioration in func’
`densny Images’ Lemons are frequently 0'-‘emed perP°"d'°”l““
`tion unassociated with acute attacks (which may continue or cease
`during the progressive phase). SPMS produces a greater amount of
`fixed neuroiogic disability than RRMS. Approximately 50% of pa-
`{gems Wm, RRM5 will have developed gpMg after 15 years’ and
`longer follow-up points indicate that the great majority of RRMS u1—
`timately evolves into SPMS Thus SPMS flPP€ars
`to represent a late-
`_
`_
`stage of the same underlying illness as RRMS.
`3. Primary progressive MS (PPMS) accounts for ~ l5% ofcases.
`These patients do not experience attacks but only a steady functional
`decline from disease onset (Fig. 359-2C). Compared to RRMS. the
`RRMS
`PPMS
`
`A
`
`[4315 359.2 Diugflosfir 5,,-1,3,,-H,,, M5
`_
`_
`_
`l. Exatmntition must reveal abjec'ri'i'e abnormalities of the
`2' Im'°I"°m°"‘ mm“ mfiw P”d°'"i“"'"”y disease °f Wm”
`mm‘ usually including (3) pyramidal pmhways’ (bi cm
`ways. (c) medial longitudinal fasciculiis (d) optic nerve..a11
`ta.-i.,, w1.,m,,5_
`’
`3. Examination or history must implicate involvemenl oftwo 01'-
`of the CNS-
`3- MRI may be used I0 document it se¢°nd1esi°n_WhF"
`,1
`of abnonnality has been demonstrable on examination. A
`three lesions ifone is periventricular in location. Accep
`toiy MRI must have either four lesions involving‘ the w
`
`must be >3 mm in diameter. For patients older than 50;;
`of the following criteria must also be met: (in) lesion stir
`(bl lesions adjacent to the bodies of the lateral Ven
`lesion(s) present in the posterior fossa.
`b. Evoked response testing may be used to document a $9?
`not evident on clinical examination.
`'
`4. The clinical patient must consist of (it) two or more 5613,3111!
`of worsening involving tlil't'eretit sites of the CNS, eachl
`24 h and occurring at least
`I month apart. or (b) gradual
`progression over at least 6 months if accompanied by:
`synthesis or two or more oli oclonal bands. MR] may be
`_
`-
`ument dissemination in time so new T2 lesion ora Gd-C
`is seen 3 or more months after a clinically isolated syndru_
`5'. The patients neurologic condition could not better be att1,'ib_
`other disease.
`ourrasrit EATEEURIES
`l. Dtgfirma MS: All live criteria fulfilled.
`
`_
`
`2. Prahahlt’ MS.‘ All five criteria fulfilled cxccpl ("-3) only 0
`zibnomialiiy despite two symptomatic episodes or (b) Olllll’
`tomiitic episode despite