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trinucleotiderepeatexpansion.
Theonsetofillnessusuallyoccursbeforetheageof20.Thecardinalclinical
manifestationsareprogressiveataxiaofgait,pescavus,kyphoscoliosis,hammer
toes, areflexia, impaired proprioception, and hypertrophic or congestive
cardiomyopathywithinterstitialmyocarditisandgranularirondeposits.
Themajorneuropathologicfindingsareinthespinalcord,althoughtheBetz
cells of the motor cortex and the cerebellar dentate nucleus are also affected
(19). The entire peripheral proprioceptive pathway is abnormal, with lack of
posteriorcolumnmyelinatedfibers,shrinkageofdorsalspinalnerveroots,lack
of large dorsal root ganglion cells, and lack of large myelinated fibers within
peripheral nerves that is best seen in purely sensory nerves such as the sural
nerve. Severe reduction in the number of nerve cells is observed within the
nucleus dorsalis of Clarke, with associated paucity of nerve fibers within the
dorsal spinocerebellar tract. Nerve fibers are also severely reduced within the
ventralspinocerebellarandlateralandventralcorticospinaltracts(Figure3.13).
Thecerebellum usuallyshows severenervecell losswithin thedentatenuclei,
withdegenerationoftheirefferentfiberscoursingthroughthesuperiorcerebellar
peduncles.Arecent, carefully executedstudyof a series of autopsiedcasesof
Friedreich’s ataxia of widely varyingageof onset and clinical course strongly
suggeststhat growtharrestof the spinalcordand thelackof largedorsal root
ganglion cells are present early in life, thus indicating hypoplasia rather than
atrophyofspinalcordanddorsalrootganglia(20).
FIGURE 3.13 Upper thoracic spinal cord in a patient with
Friedreich’s ataxia showing systematized loss of myelinated axons
within the posterior columns, lateral and ventral corticospinal tracts,
anddorsalandventralspinocerebellartracts.
HereditarySpasticParaplegia
The hereditary spastic paraplegias (HSPs) are a clinically and genetically
heterogenous group of disorders characterized predominantly by progressive
spasticweakness of the lowerextremities.Several dozen differentgenetic loci
have been identified. Most often the disorder is transmitted in autosomal
dominant fashion, but autosomal or X-linked recessive forms have also been
described.Mutationsinthespastingene(SPG4,encodedonchromosome2p22)
andintheatlastingene(SPG3A,encodedonchromosome14q12-q21)account
formorethanhalfoftheautosomaldominantformsofHSP,whereasmutations
in the spatacsin gene (SPG11, encoded on chromosome 15q13-q15) are most
commonlyassociatedwithautosomalrecessiveforms.Theonsetofillnessmay
occuratanyage,dependingonthemutation.Purephenotypesarecharacterized
by spastic lower extremity weakness alone, whereas complex phenotypes are
associated with other abnormalities, such as ataxia, dementia, seizures, visual
dysfunction,orsystemicmanifestations(21).
Pathologically, pure HSP is characterized by distally predominant loss of
myelinated axons with the lateral corticospinal tracts and, sometimes, the
posteriorcolumns(22)(Figure3.14).
AmyotrophicLateralSclerosis
Amyotrophiclateralsclerosis(ALS)isoftenincluded,togetherwithprogressive
muscularatrophy(PMA)andprogressivebulbarpalsy(PBP),underthebroader
headingofmotorneurondisease(MND),andischaracterizedbydegenerationof
motorneuronswithinmotorcortex,brainstem,andspinalcord.Thisisclinically
manifested by the development, usually in older adult life, of progressive
weakness that leads, within 2 to 5 years, to death from respiratory failure.
Dementiaoffrontotemporaltypeisseeninabout5%ofcases(23)(seeChapter
39).
A small proportion (up to 10%) of cases of ALS are familial (usually
autosomal dominant) and, of these, approximately10% to20% are associated
withmutationsofthe geneencoding copper/zincsuperoxide dismutase(Cu/Zn
SOD1)(23).AlthoughclassicalsporadicALStypicallybeginsinthelimbsand
ischaracterized,atsometimeduringthecourseofillness,bybothuppermotor
neuron (UMN) and lower motor neuron (LMN) signs, PMA, which initially
appearstoberestrictedtoLMNs,andPBP,whichseemsatfirsttobelimitedto
the brain stem, both usually progress to UMN involvement, a finding that is
reflectedinthedistributionofCNSchangesseenatautopsy.
FIGURE 3.14 “Pure” hereditary spastic paraplegia showing loss of
myelinated axons within the posterior columns and lateral
corticospinaltracts.
FIGURE 3.15 Amyotrophic lateral sclerosis showing loss of
myelinated axons within the lateral and (on one side) ventral
corticospinal tracts. Loss of spinal anterior horn cells (not pictured)
wasalsopresent.
Pathologically, LMN disease is characterized by nerve cell loss and
astrocytosiswithinthespinalanteriorhornsandbrainstemmotor(especiallythe
hypoglossal) nuclei, with striking atrophy of motor nerve roots, and UMN
diseaseis characterized by dying-back degeneration of nerve fibers within the
lateral and ventral corticospinal tracts (Figure 3.15) (24,25). With advanced
disease,themotorcortexmayalsobeaffected.Althoughsensoryfibersarenot
ordinarilyaffected,inthosesubjectswhohavebeenmaintainedforlongperiods
of time (5 years or more) on assisted ventilation damage may be observed at
sites that are typically spared, such as the lateral and ventral columns of the
spinalcordandthethird,fourth,andsixthcranialnervenucleiandthenucleusof
Onufrowicz in the sacral spinal cord (26). Cystatin C-immunoreactive Bunina
bodies, small hyaline inclusions, and ubiquitin-immunoreactive skein-like
inclusionsmaybeobservedwithinthecytoplasmofsurvivingspinalandbrain
stemmotorneurons,whicharehighlyspecificforALS(23).
AnumberofgeneticmutationsbesidesCu/ZnSOD1havebeenidentifiedin
familial cases, including TAR DNA-binding protein (TARDBP), fused in
sarcoma (FUS), vesicle-associated membrane-associated protein B (VAPB),
valosin-containingprotein(VCP), ubiquilin-2(UBQLN2),chromosome9open
reading frame 72 (C9ORF72), and chromosome modifying protein 2B
(CHMP2B).Some(TARDBP,FUS,C9ORF72)areassociatedwithdisruptionof
RNA metabolism (27–29). The C9ORF72 mutation, a hexanucleotide repeat
expansion,accountsforupto40%to50%offamilialALScases.BothCu/Zn
SOD1andC9ORF72mutationshavealsobeenobservedinasmallproportionof
sporadicALScases.Arecentstudyofalargecohortindicatesthatthenegative
prognosisassociated withC9ORF72 mutationsisdriven bymaleswith spinalonsetdisease(30).
Finally, there is both clinical and pathological overlap between familial
frontotemporaldementiaandfamilialALS,particularlywithregardtothosewith
TARDBP,FUS,andC9ORF72mutations(31).
PrimaryLateralSclerosis
Thereisconsiderabledebateastowhetherornotprimarylateralsclerosisisan
entitythatisseparateanddistinctfromotherformsofMND.Thosewhoargue
thatitisaseparatediseasedescribeasporadicmotordisorderthatisdominated
clinicallybyUMNdysfunctionwithlittleornoevidenceofLMNinvolvement,
for example, spastic weakness with no fasciculations. Survival may be
considerablylonger than forclassical ALS, oftenfor10 years ormore.Afew
undergo progression into ALS. Pathologically, although damage to the
corticospinaltractsisstriking,thepresence,onoccasion,ofsomedegreeofloss
of spinal anterior horn cells, together with the finding of ubiquitinated
cytoplasmicinclusions,suggeststhatthedisorderisavariantofALS(32).
SpinalMuscularAtrophy
Spinalmuscularatrophy(SMA)isaheterogeneousgroupofautosomalrecessive
disorders due to homozygous deletions in the survival motor neuron (SMN1)
gene on chromosome 5q13 (33). All are clinically characterized by LMN
weakness,areflexia,fasciculations,absenceofsensorysigns,andEMGevidence
ofdenervation.Theclassicalinfantiletype(typeISMAorWerdnig–Hoffmann
disease)islethalandresultsindeathatage3to18months.Thechronicinfantile
type (type II SMA) is more slowly progressive and may be associated with
survivalintoadulthood.Patientswiththechronicchildhoodtype(typeIIISMA
or Kugelberg–Welander disease) progress very slowly and may have nearnormallifeexpectancies.
Pathologically,inthesevereinfantileformthereisprofoundnervecellloss
and astrocytosis within the spinal anterior horns and brain stem motor nuclei,
withatrophyofmotornerveroots.Skeletalmuscleshowsdenervationatrophy.
A nearly identicalgene,SMN2, isableto produce onlyasmall amount of
SMNprotein,butarecentstudyhasshownthatadministrationofnusinersen,an
antisensedrugdesignedspecificallytoaltersplicingofSMN2pre-mRNAsoas
toincreasetheamountoffunctionalSMNprotein,significantlyreducesdisease
severityinpatientswithtypeISMA(34).
MultipleSclerosis
The vast majority of patients with multiple sclerosis will show clinical and
pathological evidence of spinal cord involvement, usually in association with
manifestationsindicativeofdiseaseatothersites.Inasizableproportionspinal
corddysfunction,intheformofspasticataxia,spasticparaparesis,orimpaired
proprioceptionorvibratorysensation,maypredominate.
AsisthecaseelsewhereintheCNS,thecharacteristicpathologicfindingis
thepresenceofsharplycircumscribedfociofdemyelinationwithrelativesparing
ofaxons(35).Theselesionsmaybevisibleoninspectionofthesurfaceof the
spinal cord, and may be associated with gross atrophy. As seen in transverse
section, their boundaries bear no relationto gray/white matter interfaces or to
fiber pathways (Figure 3.16). Active plaques are typically associated with
perivascular “cuffs” of both T- and, to a lesser degree, B-lymphocytes and
plasmacells,axonalswellings,lipid-ladenmacrophages,andreactiveastrocytes.
The B-lymphocytes are important because they express high levels of
granulocyte-macrophagecolony-stimulatingfactor,whichdrivesT-lymphocyte-
mediatedautoimmunity (36). The extent of cellular infiltrationwilldependon
the level of activity of the lesion. In early, active lesions, a variety of
inflammatory patterns have been described (37). Within old plaques, the
concentration of oligodendrocytes is sharply reduced. “Shadow plaques” are
thoseinwhichthestainingdensityofthemyelinisonlypartiallyreduced,and
theyrepresentremyelinationwithformationofshort,thinmyelininternodes(see
Chapter38).
FIGURE3.16Sharplycircumscribedplaquesofdemyelinationwithin
the spinal cord at C6 in a quadriplegic with long-standing multiple
sclerosis.Notethepresenceofdemyelinationwithbothgrayandwhite
matter.
NeuromyelitisOpticaSpectrumDisorder
Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, polyphasic
inflammatorydemyelinatingdisorderthatisseparateanddistinctfrommultiple
sclerosis.Thevastmajorityofaffectedsubjectsarewomen,andthemedianage
ofonsetistowardtheendofthefourthdecade.Theopticneuritisandmyelitis
may occur either sequentially or simultaneously, and over half of patients
develop permanent visual or ambulatory impairment within 5 years of onset
(38).Otherpartsof theCNSmaybeaffected.Atleasttwoseparateconditions
withoverlappingclinicalfeatureshavebeendescribed.Thefirst,whichaccounts
for some 70% of cases, is characterized by the presence of a serum IgG
autoantibodythatbindstothewaterchannelproteinaquaporin4(AQP4),which
appears to play a major role in water homeostasis within the CNS (38). The
second, which accounts for approximately one-quarter of those who are
seronegative for AQP4-IgG, is characterized by the presence of a serum IgG
autoantibodytomyelinoligodendrocyteglycoprotein(MOG)(39,40).
The histopathologic substrate of AQP4 IgG-associated NMOSD is a
necrotizing optic neuritis and longitudinally extensive myelitis in which an
admixture of demyelination and cavitatingnecrosis, an inflammatory infiltrate
containing many neutrophils and eosinophils, angiocentrically distributed
immune complex deposition, and pronounced loss of astrocytes are typically
observed (41). This disorder, which is now regarded as an autoimmune
astrocytopathy (38), also appears to occur in association with certain other
autoimmune disorders, notably systemic lupus erythematosus and Sjögren’s
syndrome.
MOG IgG-associated NMOSD, by contrast, has been characterized by
markedlyelevatedlevelsofmyelinbasicproteinbutnotofglialfibrillary acid
proteinwithintheCSF,andthusappearstotargetmyelinratherthanastrocytes
(42). Clinically, this condition tends to show less of a female predilection, a
greater degree of optic nerve involvement, less of a tendency to relapse, and
morecaudalinvolvementofthespinalcord(38,40).
TOXIC/METABOLICMYELOPATHIES
PostangiographyMyelopathy
Postangiographymyelopathyisanuncommoneventandistypicallyencountered
following aortography or, less frequently, vertebral angiography. It is a
consequenceofinadvertent administrationofcontrastmaterialdirectly intothe
spinal circulation through radiculomedullary feeding arteries. Clinical
manifestations(paraplegiaorquadriplegia)appearwithinhours.Pathologically,
thereiscentrallypredominantnecrosisthatdamagesmostofthegraymatter(3).
Thearterialsupplyandvenousdrainageareintact.Margolisetal.reproducedthe
myelopathybyinjectingsodiumacetrizoate(Urokon)intotheaortasofdogsand
concluded,onthebasisofthiswork,thatdamagewastheresultoftoxicityrather
thanischemia(43).
MyelopathyAfterIntrathecalInjections
Myelopathy may follow the intrathecal administration of a wide variety of
agents, including spinal anesthetics, alcohols, hypertonic saline, steroids,
methylene blue, chemotherapeutic agents, ammonium sulfate, or magnesium
sulfate. Pathologically, the pattern of damage is typically one of
circumferentially distributed loss of myelinated axons (Figure 3.17) (3). Later
there may be fibrous thickening of the leptomeninges. Bunge et al.
experimentally showed that simple CSF barbotage (i.e., slow, repeated
withdrawal and reinjection of minute quantities of CSF without administering
anyexogenousmaterial)couldresultincircumferentialdemyelination(44).
FIGURE 3.17 Circumferential pallor of myelin staining within the
spinal cord at L4 following intrathecal administration of hypertonic
salineforpainrelief.
ChronicAdhesiveArachnoidopathy
Fibrous thickening of the leptomeninges may result from a wide variety of
causes,includingtheintrathecaladministrationofanyoneofanumberofagents
(particularly contrast media), tuberculous or pyogenic bacterial meningitis,
traumatic injury or surgical intervention, and hemorrhage into the spinal
subarachnoid compartment. In a sizable proportion of patients, the etiologyis
unclear.Dependingonthemodeofdevelopment,thepathologicalfindingsmay
range from mild leptomeningeal opacification to dense collagenization within
thesubarachnoidcompartment,withentrapmentofnerverootsandbloodvessels
andadherencetotheoverlyingdura(Figure3.10)(3).
VitaminB12DeficiencyMyeloneuropathy
TheabsorptionwithinthedistalileumofvitaminB12(cobalamin),whichmust
besuppliedbyingestionofmeatanddairyproducts,requiresbindingtoCastle’s
intrinsic factor, which is elaborated by gastric parietal cells. Vitamin B12
deficiency may therefore be induced in a variety of circumstances, including
autoimmune gastritis, gastric or distal ileal surgery, Crohn’s disease, tropical
sprue,fish tapeworm infestation, dietary insufficiency(e.g., in vegetarians), or
inborn errors of cobalamin metabolism. Neurologically symptomatic patients
maynotbeanemic,althoughbonemarrowexaminationwillrevealthepresence
ofmegaloblasts.As the disease progresses over a period of weeks or months,
gaitataxia,impairedproprioceptionandvibratorysensation,lossofdeeptendon
reflexes,andspasticitywilldevelop,aswillanunexplainedpsychosis.
Pathologically,thediseasetypicallybeginsatmid-thoraciclevelswithsmall
fociofballooningdegenerationofmyelinsheathswithinthecentralportionsof
theposterior columns and the peripheral portionsofthe lateral columns, these
foci eventually coalescing to form large areas of myelin destruction (Figure
3.18) and secondary axonal damage, with permeation by macrophages and
reactive astrocytosis (45). Although the terms “subacute combined
degeneration” and “combined systems degeneration” are used to denote the
patternofdamage,thedestructionisnonsystematizedanddoesnotaffectentire
tractsinthemannerthatFriedreich’sataxiaorALSdo.Electronmicroscopyof
experimentallyinducedvitaminB12 deficiencymyelopathyinrhesusmonkeys
has shown that separation of myelin lamellae progresses sequentially to the
formation of intramyelinic vacuoles, degeneration of myelin sheaths, and
degeneration of axons (46). Peripheral neuropathy appears in the majority of
affectedsubjects, asevidenced by reduced nerve conduction velocity, and has
beenassociatedwithbothdemyelinationandaxonaldegeneration.
FIGURE3.18 Nonsystematized pallor of myelin stainingwithin the
dorsal and lateral white matter at spinal T8 in a patient with severe
vitaminB12deficiency.
Chronicexposuretonitrousoxide(NO)mayproduceasimilarclinicaland
pathologic picture. NO appears to inactivate methionine synthetase, a vitamin
B12-dependentenzyme(47).
INFECTIONSWITHINTHESPINALCANAL
SpinalEpiduralAbscess
Spinalepidural abscess formationtypicallydevelops in the presenceof one or
morepredisposingfactors,suchasdiabetesmellitus,chronicalcoholabuse,HIV
infection,aprioroperativeprocedure,placementofastimulatororacatheter,or
sepsis. It occurs more frequently posteriorly than anteriorly and in the
thoracolumbarthaninthecervicalregion.Staphylococcusaureusistheetiologic
agentin at least two-thirds ofcases(48). Clinically,the classical clinical triad
consistsofbackpain,fever,andneurologicdeficit(weakness),althoughnotall
componentsarealways present.MRI iscurrentlythemostsensitive methodof
detection. Hematogenous dissemination, seen in approximately half of the
affected subjects, typically results in an exudate in which neutrophils
predominate, whereas contiguous spread from an adjoining focus of infection
(such as vertebral osteomyelitis), which accounts for another third of those
affected, often results in a mixed inflammatory response that contains an
abundanceoflymphocytesandplasmacells.Themechanismbywhichthespinal
cord is damaged is unclear. Although Feldenzer et al. (1988), in their
experimentalanimalmodel,foundevidenceofdirectcompression(49),studies
at autopsy have shown the presence, on occasion, of thrombosis of small
leptomeningealarteriesandveins(32).
SpinalSubduralAbscess
Spinalsubduralabscessformationisconsiderablylesscommon. Mostof these
lesions occur at cervical or thoracic levels and, as is the case with epidural
infections, Staphylococcus aureus is the most commonly isolated agent (50).
Although in most instances. infection is believed to be the result of
hematogenousdissemination,aprimaryfocusatanothersiteisoftennotfound.
Again,themechanismofdamagetothespinalcordisdebated(i.e.,compression
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