TIIE SYNDROUIC NATT'RE OF AMYOTROPHIC ATERAL SCLEROSIS B . M. Patten Baylor CoLLege of Medieine Houston Teaas, U.S.A Introductlou Le t me start s'lth a confession' I d o not,be11'Y"-::^::Yll'llll"ur"- ,.."'li'"li.iilii."';;r" "s'a o bother 1 :' b":-":Y..i-::"::::::"t11" i:ii:?'":'fi';ilil""';"i'"-'a""";;;;: :,1" :1 1Y?:::"1":i:ii.il"" * :iii:i":" iil:" l:;';"""-"illii:il':1""1:':, ::, :*:;:'.::::i:ill" fi:::lH.;H:';"i;;l;;:";i'd;;;:;l!; i :* 1f :u:i;.'::"':::"1:":' ffii::fi:?-;;;;;;;nents a nd he unusual :i":: :1'1: 1",1"?.1?,i." ;:?ilil:"il"".'T;';-""-"a"""'"se e;1ys: 1: ::':1::"T:":: il:tit: eluaEe cau5c. . " :: :^^;-:-;;-:, wt --:e rhar I a m n o t ietailed evaluatlon of each patient, with a clear conscl-en( ^ - ^ ts ^^ ^€ a\r..ess -,-+'con- ;;:ffi;.;;;-;;-;;;";-"nd wtitr.'""":lil::-"Tf::'1::::,:: :Sff astlng tlme oruoo"y "r d wlih- reasonable expectation.of s\{ge9P'----d- cor- duct h e nvestisatl;"-;; ii th e patlent'" ltl: 1"t:io:1-ll lii'lliil;":"li i:':r::; l::::"fi;';"'..1-t"-.i";p'";-;; much rime a nd monev evaluatlng each l^A ?)nref 6T qiil ilJ $rt iI,I i.ril atlent with AL S as . I would have spent i f that patlent ha d cancer or leukernia or some otner usually serlous an d often fatal condition' In this short Paper, I te11 wh y AL S must be a syndrome an d no t a disease an d what titi"!" "a " prodt'"" th e syndrone' I outline th e current approach used to .."ii"tt paiients with tire AL S syndrone an d lllustrate th e results o f that approach wlth some c"st "*t*ples' The-Paper closes with what I consider the-mlnimum evaluation of patients presenting with motor neuron dYsfunction' Th e complexlty that encomPasses th e AL S situatlon never ceases to amaze me . Constant ult""tio" io att"fi dogged perslstence in followlng up clues an d abnormaiiii."--iri break thls "yrrliot. into subgroups that ca n be studied an d understood' Why AIS must be a SYndrome A syndrome is a constellat{on of signs an d symptorns' Th e word itself comes from th e Greek meanlng a running tlgether' So when a of signs an d syrnptoms ru n Eogether like "nl"t, an d lower motor neuron signs it means there is failure or-ito"" p".t" Ll th e nervous syscem. AL s is no more a dlseasethanrenalfailurelsadisease.whe,,t-hekldneysfailthepatient shows characteristic an a easity identified syndrome of uremia. rn that case th e doctor ao"" ,rot interlst himself in merely diagnosing renal failure. Instead'-i"-tt"t" to know th e cause' He wants to find which on e
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i:ii:?'":'fi';ilil""';"i'"-'a""";;;;::,1":1 1Y?:::"1":i:ii.il""*:iii:i":"iil:" l:;';"""-"illii:il':1""1:':,::, :*:;:'.::::i:ill"fi:::lH.;H:';"i;;l;;:";i'd;;;:;l!;i :* 1f :u:i;.'::"':::"1:":'ffii::fi:?-;;;;;;;nents and heunusual:i":: :1'1: 1",1"?.1?,i.";:?ilil:"il"".'T;';-""-"a"""'"se e;1ys:1: ::':1::"T:":: il:tit:e l u a E e c a u 5 c . . "
: : : ^ ^ ; - : - ; ; - : , w t- - : e r h a r I a m n o t
ieta i led evaluatlon of each patient, w i th a c lear conscl-en(^ - ^ ts ^^ ^€ a\r. .ess -,-+'con-
duct he nvestisatl;"-;; ii thepatlent'" ltl: 1"t:io:1-ll lii'lliil;":"lii : ' :r::; l: :::"f i; ' ;" '. .1-t"-. i";p'";-;; much rime and monevevaluatlng each
l ^ A ? ) n r e f 6 T
qiil
ilJ$rtiI,Ii.ril
atlent with AL S as . I would have spent i f that patlent ha d cancer or
leukernia or some otner usually serlous an d often fatal condit ion'
In this short Paper, I te11 wh y AL S must be a syndrome an d no t a
disease an d what t it i"!""a "
prodt '"" th e syndrone' I outl ine th e current
approach used to .."i i"t t paiients with t ire AL S syndrone an d ll lustrate th e
resu l t s of that approach wl th some c"s t" * t *p les '
The-Paper c loses wi th
what I consider the-mlnimum standard evaluation of patients presenting with
motor neuron dYsfunction'
Th e complexlty that encomPasses th e AL S situatlon never ceases to
amaze me . Constant ult""t io" io att"f i an d dogged perslstence in followlng
up clues an d abnormaii i i ."-- ir i break thls"yrrl iot.
into subgroups that ca n
be studied an d understood'
Why AIS must be a SYndrome
A syndrome is a constellat{on of signs an d symptorns' Th e word itself
comes from th e Greek meanlng a running tlgether' Sowhen a grouP of signs
and syrnptoms run Eogether like"nl"t,
and lower motor neuron signs it means
there is failure or-ito"" p".t" Ll th e nervous syscem. AL s is no more a
d l s e a s e t h a n r e n a l f a i l u r e l s a d i s e a s e . w h e , , t - h e k l d n e y s f a i l t h e p a t i e n tshows characterist ic an a easity identif ied syndrome of uremia. rn that
case th e doctor ao"" ,rot interlst himself in merely diagnosing renal
failure. Instead'- i"-t t"t" to know th e cause' He wants to f ind which on e
of the causes of kidney fallure, among hundreds, is working in th e patientin question. An d if he flnds a correctable problen, th e specialist wll lt reat with a dogged tenacity to try to reverse th e disease an d solve th epat l "ent 's prob len.
rn th e sanDeway, when motor neurons fail th e patJ.ent shows character-ist ic an d easily ldentif led signs and symptoms of motor neuron dlsease, bu tth e physician should no t be satisf ied in making that discovery no r inclasslfying what notor neurons are not worklng. Ou r focus nust be on acareful search fo r a cause of the motor neuron failure. rf we find atreatable cause' we must treat wlth a dogged tenacity to reverse th ed isease and to so lve the pat lent ts prob lem. r t appears so obv lous therear e many causes of AL S that reviewlng th e evidence seems tr lvial. Never-the less , I do rev iew i t here for purposes of expos i t ion .
Brlef Su-ary of the Known Causes of the ALS Syndrone
There ar e several dif ferent types of lnherited AI-s including a se xllnked and autosonnal dominant form so there must be different genes con-t ro l l ing the express ion of the condl t ion I l ] . Th is nus t automat ica l ly mean
there are several types of inherited ALS, each r^rith it s ow n enzyme defic-iency or structural cause. we know that hexosaminidase A deficiencv ca npresent wi th the s igns of motor neuron d isease wi th upper and lower moEorneuron d isease due to GM2gangl ios ide in the bodles of neurons [2 ] . Th is isjus t one forn of the d lsease due to a metabo l ic les lon. I sc reened 56consecut ive pat ients before r found ny f l rs t case of Hex A def lc iencypresent ing as ALS. rn teres t ing ly that pat ient had to ta l Hex A def ic iencywhen tes ted wi th the ar t i f i c ia l subs t ra te , but was only 502 def lc ient whlntes ted wi th the natura l GM2gangl ios ide subs t ra te , exp la in ing why he had anALS syndrone an d no t Tay-sachs dlsease. Lead poisonlng ca n produce ALS. Adeta i led case repor t by s inpson publ ished in 1966 proved that po in t [3 ] .s impsonrs pat ient , a welder w i th anemla, had excess lve excre t ion of lead lnurine on EDTAwash ou t and made a complete recovery after deleading treat-ment . That pat lent remai .nswel l 18 years af ter h is d isorder s tar ted(persona l conmunicat ion, J . s impson) . r have seen and t reated severa l
si"milar cases. They are rare, but when found an d treated they na y recoveramazingly well.
Hyper thyro id ism can produce a pic ture l ike ALS in every way, exceptthe ALS goes away, in most cases when the hyper thyro id ism stops i4 l . Hyper_parathyro id ism produces ALS which reverses in the ear ly s tages , i f somlonecor rec ts the abnormal icy in ca lc ium netabo l isn [5 ] . cerv ica l cord com-pression an d other diseases can sinulate AL S by causing upper an d lowermotor neuron s igns and syrnptons , a condi t ion d iscussed in deta i l bys tor tebecker [6 ] . sonet i -nes , the pat ient has severe cerv ica l and lumbarspondy los is wi th mul t ip le nerve root compress ions g iv ing fasc lcu la t ions andat rophy and other lower motor neuron s igns in the lower ex t remi t ies , as l tuat ion i_ l lus t ra ted be low.
Recent ly , severa l authors have assoc ia ted ALS wi th p lasna ce l l d iseasean d monoclonal ganmopathy[7]. rntensive treatment of th e monoclonal garDmo-pathy can reverse or inprove the cond i t ion in some cases [g ] . r f a rnono-clonal gamnopathy ca n cause ALS, then llE_sust follow that a polyclonalganrcgathy ca n do Eh e same - an A.LSof 3aa1sD e t o w l y l .
Many papers and books cover the clinical diagnosl,s of ALS indeta i l [10-12] , but , I wonder how valuab le the energy spent on deta i led
history an d physical examj.nation ls . The diagnosis is usually obvious froninspection and routlne examinatlon shows the characterist ic signs of upperan d lower motor neuron dlsease with relat ive sparing of cerebellum, sensory
systens, and extraocular movement. The clinical f lndlngs merely show thatthe motor neurons are in t roub le . Bet ter to focus on f ind ing the cause byextenslve laboratory i-nvestigation. Nevertheless, some interest ing
c l in ica l features and the i r poss ib le in terpre ta t ion appear ln Tab le l .
Take these as rules of thumb which often work, but sometimes do not.
Laboratory
The laboratory tests j-mportant in investigating the ALS symdromeappear in Table 2 with some comments about their signif icance. This is
what I consider the usual evaluatj.on, bu t again these are rules of churnb.A conple te and deta i led laboratory eva luat ion is more essent ia l to theunderstanding of ALS than any other nedical procedure lncluding history andphysical examinatlon. I l l lustrate this point wlth the Een case examples
that fo l low.
L:r0ftD Le I
A 35 year o1d phys ic lan noted the gradual onset and cont inued pro-
gress ion o f musc le weakness , a t rophy , fasc icu la t ions , and cramps. 0nexamlnatlon, he had hyperref lexla, knee and ankle clonus, and severe weak-ness o f the prox imal and d is ta l musc les of upper and lower ex t remi t ieswi thout sensory loss . He cons idered that he had ALS, buE re fused fur ther
Tab le 1 .C l in ica l C lues that Sugges t Atyp ica l
ALS
Exposure to lead.
Long-term surviva].
Exacerbations and improvements.Dry mouth and dry eyes and dry vag ina (S jogrenrs syndrone) .Skin rash part i-cularly over the elbows and knees and knuckles.Renarkable worsening with exercj.se and improvement with rest.
; - \ - Glove and sEock ing sensory loss to pin and v ibrac ion.
[€ R""o" ia ted other d iseases o f auco innune or ig in par t icu lar ly severe insu l in'
dependent d iabetes .
D ip iop ia .
En larged thyro id .
Lynphadenopathy.Excess ive ly rap id down-h i l l course.
Pos i t i - ve tens i lon tes t .-Poor range of mot ion o f neck (may mean spondy los is ) .
- P tos is (1ook for the ra t roph ic form of myas then ia grav is r ) .- Excessive weight loss (suggests malabsorptlon an d secondary hyperpara-
thyroidism). Sone patients rdith pancreatic insuff iciency have been
nisdiagnosed as ALS. When there i s the slightest doubt do the
appropr ia te tes ts to make sure that d lagnos ls is ru led out .
\--. Diabetes urell i tus especlally of recent onset. This ls often mistaken fo r
ALS and these patients have both diabetes and usually an autoimmune
inf lamnatory neuropathy. They should be treated with Cytoxan if the
Table 2. Sunmary of Laboratory Items that should be done ln AL S
Blood tests
CBC, ESR, NaKCO2C1,SMA-15 (should include
T3, T4, TSH and other thyro ld tes ts .Parathyroid hormone leve1.Blood lead, mercury, alumlnum.Rheunatoid factor, antinuclear antlbodj.es,
resol-ut ion an d
calcium an d phosphate).
compliment levels, serumpersonal lnspectlon of the
Serum amino acld screen.apr
Ant iacety lcho l ine receptor ant ibody t l te r .Hepat i t i s sc reen for Hepat i t i s B sur face ant igen
Tissue biopsies
Musc le b iopsy .Sura l nerve b lopsy .
B1-ops iesof mi"nor sa l ivary g lands i f S jogrenrs is suspec ted.
Other tests
Magnet ic resonance of bra in and sp ina l cord .sp ina l tap wi th s tud ies for er "ec t rophores is and o l igoc lona l bands .
E l -ec t romyogram ook ing for decrements wi th s t imula t ion at 1ow (2 Hz) ra tes .
e v a lu a t lo n b e c a u s e he s a id h e d ld n o t fb e l i e v ein d o c to rs ? . o v e r a s ix
month perlod he declined so that he could no longer get up from a squat an dh e h a d s h o r tn e s s o f b re a th o n wa lk in g a c ro s s a ro o m. Gr ip s t re n g th d e te r -iorated fron 163 pounds to 80 pounds in fhe dominant r ight hand. A phys_lc ian fr iend drew thyroid tes ts when he saw ho w much excessive food the
p a t le n t a te . T h e T 4 w as 2 3 a n d th e th y ro id s c a n d i f f u s e ly o v e ra c t i v ee s ta b l i s h j -n g th e d ia g n o s is o f Gra v e r " d i " "u . " . T h e p a t ie n t re fu s e d ra d io -th e ra p y , b u t to o k P TU wi th a re tu rn t o e u th y ro id i s m , a 2 3 p o u n d ! /e ig h tg a i -n , an d a n in c re a s e i n g r ip to l 12 p o u n d s . T he h y p e r re f le x ia a n d c lo n u sd is a p p e a re d a n d h e re ma in s in re rn i s s io n 9 y e a rs la te r .
Conrment: pyramidal tract defic i ts an d polyneuropathy in hyper_thyroid ism in combination cl in ical ly mirn ics ALS especia l ly when the hyper-th y ro id i s m i s lo n g n e g le c te d a s 1 n th e c a s e h e re . i ^ / i t h c l r re c t io n o f th eh y p e r th y ro id i s m , t he n e rv o u s s y s te m p ro b re ms d is a p p e a r i n mo s t c a s e s [4 ] .
Eronple 2
over three years a 4I year old man noted progressive weakness an derasting of rnuscle an d weight loss of l0 kilograms. on examlnation, he
cou ld not l i f t legs agains t grav i t y nor s tand a lone wi thout suppor t .Although al 1 muscles were i-nvolved, proximal muscles were weaker thand is ta l and lower ex t remi t ies were weaker Ehan upper ex t remi t ies . Therewere fasciculat ions in the atrophic muscles of the arms, but not ln thetongue. Reflexes were hyperactive vrith knee and ankle clonus. A11 testsof sensory, cerebellar, an d cranlal nerve function gave normal results.The clinical pi.cture wa s ALS, a diagnosis supporced by the f inding ofsevere neurogenic atrophy in th e muscle biopsy. Because of complalnts ofjoint pain, he appeared in the rheumatology clinic where his blood bicar-
t'
p la c e t o r mo n o clate to r monocLonal gamopaff if lHexosaminidase A an d B.
bonate na s discovered to be slight ly depressed to 19 meq/L. Further
evaluation revealed a Fanconl syndrome with aminoaciduria, phosphaturiar,,
and uricouria. We admitted hin to the clinical research center and studied
him in detail to f lnd that phosphate rePlacement alone corrected hi s
nervous system dlsease. As long as the phosphate continued, he renained
wel1.When th e phosphate stopPed th e ALS syndrome returned. Four years
later while st i l1 taking replacement phosphate, he remains ellnically
normal and worklng ful1 tine.
coment: Dr. Mallette an d I reported thls case in detail to Prove
once an d fo r all that a metabolic lesion can cause a reversible AL S syn-
d r o r n e [ 1 3 ]
ExanPLe 3
A 55 year old neurosurgeon noted atrophy and weakness of hi s upper
extremlt ie; and fat igue while working. He examined hirnself an d found
hyperreftexia an d considered that he had ALS. 0n exaninatlon he ha d
"iiopiryan d fasciculat ions of the extremit les, bu t th e tongue wa s normal.
fh e ief lexes ltere hyperactive, bu t there was no babinski slgn' EM Gwa s no t
done, bu t muscle Ufopsy showed snall angular dark f ibers characterist ic of
n"rrrog"tr l" atrophy. The sign ou t diagnosls agreed to by Eh e attending
ne'rologist (nyseit) an d th e residents was ALS. Three months later he
developed diplopia an d wa s readrnit ted. The tensilon test wa s posit ive and
he had- antiacetylchollne recept.or antibodies ln his blood. Subsequently'
he wa s treated wlth nestinon, prednisone, cytoxan, an d thymectomy' Th e
d i p l o p l a d l s a p p e a r e d a s d l d h t s a t r o p h y a n d h y p e r r e f l e x i a . N o w s e v e n y e a r safier- th e onset of hi s ll lness he is without evidence of ALS.
coilment: thls patient ha d an autolmune disease with features of
nyasthenia gravis .n a u,s. with aggressive treatment of the myasthenla'
t ire AL S synarome dlsappeared. Therefore, th e patient probably ha d an ALS
syndrome tf autoinmunl- orlgin. The antiacetylchollne receptor antibody wa s
a marker fo r th e Presence of autoiunune mechanisrns in hj-s condit ion'
Enonple 4
W G , a 6 0 y e a r o l d m a y o r o f a s m a l l c i t y r d e v e l o p e d p r o g r e s s i v e w e a k -
ness of upper in d lower extremit ies with atrophy and fasciculat ions an d
hyperref l lxla. There were bilateral bablnski signs an d clonus. He wa s
"u"t '. t"dwlth c1lnical examinations an d EM Gat the Mayo Cllnic an d felt to
have ALS. When I saet hl m fo r a second opinlon, I agreed with th e dlagnosis
an d did a muscle blopsy an d spinal f luid examlnation. Th e nuscle biopsy,
frorn left blceps, showed severe neurogenlc atrophy' Th e spinal f luid wa s
normal. Later, he consulted another neurologist wh o dl d a NMRscan of the
brain which showed th e lesions of urult iple sclerosis. RePeat spinal ta p
no w showed oligoclonal bands. He r.tas t ieated with three courses of l0 days
of ACTI{a.nd cytoxan wlth improvement of strength an d abil ity to walk. over
th e ensulng years hls improvement continues'
Coxment: magnetic resonance imaging enables th e detection of subtle
cases of white natter dlsease whicheluded detection previously. There is
a form of mult iple sclerosls whlch ninics ALS as il l-ustrated by this
p a t i e n t . s u s p e c t t h a t t y p e o f A L S i f t h e p a t i e n t h a s a n o r m a l t o n g u e , s l o w
course, abnormal rdhite matter lesions on th e magnetlc scan, or oligoclonal
i;.;jw":.:$l;'':l":i"ii.:::i.lll;'"]'i'i:::.::o x l d a t i v e s t a i n o f t h e m u s c l e b i o p s y i n d i c a t i n g t h a t i n t h i s c a s e t h ernult lple sclerosls wa s associated lt ith peripheral nervous system dlsease
A 24 year old.wompn developed severe progressive weakness of th e;::'ff:fiff.H'1,:;';fl:f";::,i31:'T.':.1:"^".;F-*;-;;";ue.(8rossa1trophyas.havingi.*."""*;,".,r.".oi""r"li"Xi:,:ffi;:. iil..1;ff";";::jtrj:nd conductlon velociri""
""r"'nol
obtatnabl".-r, i i""rJiroo",
showedsevereeurogenlc
atrophy, bu t th e spinal ir.ria"nor"a
,..t"i increase in pory_ronar- ganmaglobulin. Becausl oi-aii" t i"ai"e-"hJ-iI]"ru.a"d
on alternateay predni-sone. Th e inprover".ri-t""_r""""r"l i ig-ri l i rr.""", atrophyisappearln* r"u
:n:-r"ir"". lri";-;r*_inabil irv to sii up or rurn i. ned to walking an d artendi.rg loffEg.. Recently, she gave blrth ro aormal infant' N-ot, 9 y"".i l"t"r'"h"-.orrt i.rues to dJ welr, although sheil"";;ii":"ak
with i.ip! ur."i*i6'pJ,r,,a" .,a"-".Jiri-"lu roo. dropswhen
comment : per iphera l .neuropathycan produce a c l in lca l p ic ture thatesenbles noror neuron dlsease. u"a' air"
"prr, . ii i" i i"."."rned, r thouehthi s patlenr had irrl" r"t"i". *.ir,". p".ip;;;"i*Ioiai.io' that ca n b!i s taken for notor neuron d isease is the i " " . " " t - ; i " ; ; ; . There theatlent shows fasclculat lons
"ra,,r".1" atrophy, i"i-"Ji"rry responds toreatment as is i l lus t ra ted by the , ru*a
"" " " .Euanple 6
A 52 year ord ma n devel0ped muscle weakness an d atrophy with severeeneralized fasciculat lons. ir," F.""r"u1atlons""r"
i" ' ir ," upper limbsspec ia l ly on the r lght s ide. On examinat lon, he f ,ua- " . fgUa foot drop,astlng of hands, arms, shoulders and proxlural muscles oi arr" lower 1lmbs.endon ref lexes were br isk on the i " i to , t * b i la tera l e* i " r r "o . prantaresponses (posit ive babinski slgns). He wa s ai"g"o""a-;J n.rr irrg A_LS ndr led on TRH and then cyc lospor in wi thout benef i t .
At ag e 55 when r sa w hi n ln consultat ion r di d spinar anesrhesla.nder comple te sDinar anes thes la ar r " i " . r " " no change in h is severe fasc i_u la t lons , but t i re EMGd1d, ro t" tor - i r ip re ts
or couprets . wr th Di lant i .n henproved conslderably wlth ro"" or ni " cramps an d a return in hi s abtrity
""J.n","a".,r"rop"a-ii lrru". Th e Tegretolas disconrlnued and. rro_other ag"ni"-1cror,"""p"r-1.,I oii"""r rrled rrirhouronplete control of hl s ra"cic,rrrcion". A sural ,r"ru"-biop"y showed os sf myellnated and unmyellnated fibers an d some
"*or.t-"i i.rg"". Th e muscleiopsy showed neurogenic atrophy. Blood ga"es showed compensated res_i ra torv ac ldos ls - He returned- to canada ' ; ; ; " " ; ; ;= ; t " r " ' i " r " o f rssacsryndrome was dlsputed-and, the a i "g"o" i " o f ALS re ins ta ted. Later hl sed ic lnes were a l tered and he aet l r io ra ted and died. e i - " , raop"y (Dr H. v .inters' hrrit ten conmunlcation) there was_no norphologic evidence of motoreuron disease in braln or spinal cord. There wa s"
i"". ,rr iars of th erachial plexus an d a severe eoslnophil ic nyocardit is.
coument : rssacsr can 100k l ike ALS. when there is a doubt aboutthelagnos ls the bet ter par t of va10r is to t reat w i th Di lant ln and see i f theatient improves 1n strength as th e fasclculat i-orr" a.rJ-rrr"cle cramps comender control. Thls patient probably ha d
A 22 year old mar: wa s first seen at age 14 complaining of progresslve
weakness an d atrophy r:f the upper an d lower extremit ies' He ha d been
evaluated with muscle blopsy an d EM Gan d felt to have Progressive spinal
muscl-e atroPhy' exceprE ha tth e repetit ive st lmulat ion studles showed
d""."t .rrt" lo low stinulus rates as ar e seen in myasthenla gravis' He wa s
nresented at th e Neurrcmuscular Disease conference at Baylor an d felt to
f, ; ; ;"; ; i ;" i- .""""i", ,arrophy. Ar rh e time he wa s wheet chair bound. r
i i""a"i hi n with Mestinon, an d prednlsone on rh e theory he night have
ry"rat"oit gravj-s, bu t there tt i to inprovement' Antiacetylcholine
,l."paot"rr l ibodi""
were no t detected in hts blood' Subsequently' r
treated with cytoxan an d thymectony an d th e Patient ha s undergone pro-
gressive improvement. tt e is no w normal vlth no atrophy or weakness an d
plays basketba l l e tc .
Comment: no questlon that thls patlent recovered, bu t why? He
protably ha d a courbination of motor neuton dlsease associated with
iy."at"ir i. . Both con.dlt lons responded to lntensive an d prolonged treat-
nent .
EranPLe B
L 46 yeat o1 d woman developed severe atrophy an d weakness with signs
of upper motor neurorr disease includlng clonus' hyperref lexla' an d a
bablnski sign. Tw o rreurologlsts thougf,t"h "
ha d AL S an d so dl d I' Sh e wa s
adnitted to th e hospjltal where nuscle biopsy showed neurogenic atrophy an d
th e myelogram an d sp:Lnal f luld,were"ott"i '-
Durlng th e tw o week admission
s h e d e v e l o p e d s w e l l i r r g o f t h e l y m p h n o d e s l n t h e n e c k a n d b l o p s y o f t h e s e
showed replacement of th e nodal architecture with srnall lynphocytes'
Because sh e comprained of dr y mouth an d dr y eyes an d dry-vagina, a biopsy
of th e l ip minor". i1"".y
glands wa s done ind showed lnf lammation charac-
terist lc or s5ogren;,"y.rdionl".
sh e wa s treated wlth lntravenous cyEoxan
a n d m e t h y l p re d n i s o l o i n e w i t h co r n p l e t e r e m i ss l o n o f t h e l y r a ph a d e n o p a t h y ,
i m P r o v e m e n t o f t h e d r y m o u t h , a n d r e m i s s i o n o f t h e A L S s y n d r o n e . S u b s e -quently sh e ha s ha d tw o more occurrences of an AL S like picture wlth well
documented upper an d lower motor neuron signs' one with an d one wlthoutEh e
lyrnphadenopathy. Each tlme sh e respondea wittr complete remission of th e
A L S a f t e r C y E o x a n a n d r n e t h y l p r e d n l s o n e t r e a t m e n t t r e a t m e n t . N e u r o l o g l c a l l y
she is now normal i t . " " y " . . " a f ter Ehe s tar t of her d isease, but she has
developed rheumatoid art irr it is of th e hands an d he r rheumatoid factor'
p rev ious lY negat ive , i s Pos i t ive '
Comment: watch ou t fo r Sjogrenrs syndrome sinulat ing ALS' [ ' le have-
seen tw o other sj_mi1.ar cases ,t t ar y eyes an d dr y mouth,and th e cllnical
pi"irrt" that other F'hysicians called ALS' A1 1 responded to treatment'
A tear test an d th e rlse bengal test ar e indicated ln an y AL S patient
wh o complains of dr1' eyes' If those tests ar e poslt lve' then th e patlent
should ge t a mlnor-i,"f it ' t 'y gland biopsy to prove the.diagnosis of
Sjogrenrs followed tr y j-ntensive treatrnenc of th e autolmmune condit ion'
ExanPLe 9
At ag e 53 this ttoman noted weakness in th e hands followed by atrophy
an d weakness of ti " upper extremit les' Withtn si x rnonths' both lower
extremit ies were also involved with atrophy, weakness,_and fasciculat ions'
S o o n t h e r e a f t e r , s h . e d e v e l o p e d d i f f i c u l t y c h e w i n g , s w a l l o w l n g ' a n d t a l k i n g .
on examlnatrorr, . i '-ug"-54 sire ha d a hyperactive ja w jerk, atroPhy' weakness
an d fasciculat lons of th e tongue, t".L"a atrophy, weakness an d fascl-
culat ions of th e museles of th e upper an d lowlr extrenit les with clonus'
crossed adductors an d bilateral bibinskl slgns. sh e wa s unable to ro11
over i 'n bed, much less sit , stand or wa1k. There were Do sensory, cer-ebe l la r or sph inc ter abnormal i t ies .
B100d an d cs F showed a monoclonal gannopathy of th e rG G kappa type.we treated he r intensively with 15 plasna exchanges, daily cytoxan an dprednisonewith no change in he r condit iorr. treltment wa s abandoned aftersh e became leucopenic.
conment: this is no t th e first case of AL S associated wlth a nono-clonal gannopathy that,falled to respond to treatment. Somepatients donot respond, but some do as i s i l lus l ra ted by the nex t case[g ] .
Eranrple 10
At ag e 57 this woman noted diff iculty in swallowlng, forrowed bytrouble walking. within on e year, sh e 10st 35 pounds, Irra ir"a dif f icultyclinbing stalrs, gett ing ou t of a chair, an d bathing. sh e compralned of apoor appetite an d a peculi.ar metall ic taste in he r mouth. on examinationat ag e 58' she showed severe atrophy an d weakness of th e muscles of upperan d lower extremiries with some dysphagia bu t otherwi-se normal crani.alnerves . Deep tendon ref lexes were normal , and
there were no cerebe l la r ,sensory ' or sph lnc ter d is turbances . Her fa ther d i -ed of leuken ia and hermother d led of cancer of the co lon.
Brood work showed a monoclonal rG G of kappa type an d sh e ha d diffuseosteoporosis of th e vertebral column. Muscle bropsy showed moderate neuro_genic atrophy. Sh e go t worse an d became so weak sh e could no t l if t he rIegs against gravity. The reflexes became hyperactlve !r ' i th abnornal spreadthus givlng th e clinlcal appearance of ALS. A bone marro' showed greaterthan 52 plasma cel1s so she wa s started on a program of vincri.st in,Melphalan, an d prednlsone because it appeared thit he r AL S wa s headed fo r afa ta l te rn inat lon. Her re f lexes becane hypoac t ive , but her s t rength andmuscre bulk dramatically improved so that sh e wa s no w able to holJ he r regsagai'nst gravlty fo r over 40 seconds, an d sh e could c11nb stalrs, get ou t ofa cha i r , do her ha i r , get up f rom a squat , and swal low normal ly . Thestrange abnormal taste in her mouth di,sappeared. over th e course of threemonths, sh e gained about 20 pounds in weight an d returned to work. Th econcent ra t ion of M prote ln in her serum was reduced to about 502 o f i t sln i t la l va lue. she cont inued to do wel l fo r about four months unt i l sheagaln noted increasing weakness an d fat i-gue. This t ime sh e wa s treatedwi th in t ravenous cyroxan (750 mg each, to ta l dose = 1500 ng) and 5 plasmaexchanges of 2 l i te rs each. co inc ident wi th th is t reatment there was agreater than 502 reduc t lon in the seruu leve l of the monoc lona l pro te in , atw o fold increase in grip strength, an d a 592 i.ncrease ln re g hoidirrg t ineand a re turn of her head hold ing t ine to normal (greater than 60 secJnds) .she dld well fo r another 5 months an d then developed a cancer of th e 1ung.sh e died of Ehat disease wi.ch a recurrence of th e Ar,s llke picture.
comment: sh e is no t the f lrst patlent with th e AL S syndrome associatedwi th a monoc lona l pro te in to respond to t reatnent [g ] . She probably had aparaneoplast ic syndrome wi.th th e monocl0nal protein a response to th e
presence of an occu l t cancer of the lung.
Concluslons
AL S is no t a disease. It is a syndrome suggesting the patient ha sdysfunction of th e lower an d upper motor tte.trott i. we know in rareinstances that this syndrome ca n be caused by cervical spondylosis, heavymetal intoxicatlon, by hexosLninidase deficiency, an d by plasma celldlsease. An autoinmune form of Al,S probably also exists.-
W e s h o u l d s t u d y e a c h A J , s p a t i e n t w i t h n u l t l p l e b l o o d t e s t s a n d o e r v e
and nuscle biopsles in the hopls of picklng up the few who nay beneflt from
treatment. My motto ls to spend as much tlme and energy and rnoney evalu-
atlng an ALS patlent as we would have spent if that patlent had leukenia or
lor"-ott . . serlous an d usually fatal disorder'
If a patient nlth clinicalAL S ha s signif icant.autoilmune dlsease'
then I se e no reason that we should not tr lat them inteoslvely. Hopefully,
th e AL S wiII inprove or remit ' If we discover an y oEher serious abnorm-
a l l t y d u r i n g d e t a i l e d e v a l u a t i o n ' w e s h o u l d t r e a t l t w l t h a d o g g e d t e n a c i t yln the hoPe the ALS night lmProve'
Acknowledgeoent
This work wa s suPPorted by gifts from The George an d lrene Lindler
Foundatlon an d a gift from Bruce an d Burlene Bauman'
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