The Syndromic Nature of ALS

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TIIE SYNDROUICNATT'REOF AMYOTROPHIC ATERAL SCLEROSIS

B. M. Pat ten

Baylor CoLLegeof Medieine

HoustonTeaas, U.S.A

Introductlou

Le t mestart s'lth a confession' I do not,be11'Y"-::^::Yll'llll"ur"-

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: : : ^ ^ ; - : - ; ; - : , 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-

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wlih- reasonable expectation.of s\{ge9P'----d- cor-

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

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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 .

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Current Approach to the Dlagnosls of ALS

L 'LLNLCAL

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

nerve biopsy shows vasculit is or inf lannation.

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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.

L O 2



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

causing true muscle atroPhy'

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EronpLe 5

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

;:,:";:,1#"511;".lii":'T:::i::to''"-ina"*"nt"'"au"tio,, orhat heyaddedo.i'" ..".i,"nr prosran."r.nri"lll":";:ii:":ll.tili;"ti3l!::l_"."ated, refrexes becamebriJk agatn

""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

"na.rtoinmuneJl""u". that wa s

;:: : : : : '$"*:, :1proiuclng p"'ipt '" ih- nerve disease rhat resenbled th e

04



EnatQLe 7

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

f'''ta r I

0t;

tlilTurf*ril

ri:ll

105



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.-

r06



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'

References

l . A. Schanen, J. Mlko l , C ' Guizo iu ' C ' V l ta l ' ! 1 ' Coquet ' A ' Lagueny ' J '

J u l i e n , a n d } l . H a g u e n a u , F o r m e f a m i l i a l e l j - e e a u s e x e d I a m y o t r o p h i esp ina le ptogt " " " f i t de i tadu l te ' Rev 'Neuro l (Par is ) ' 140:720-727( 1 9 8 4 ) .

2 , M. Kaback , J. M i les , M' Yaf fe , H ' I tabash i ' H ' Mc ln ty re ' I "1 ' Goldberg '

a n d T . . M o h a n d a s , H e x a m i n l d a s e - A ( H e x A ) d e i f i c l e n c y l n e a r l y a d u l t -

hood: a""*

ayp" of G1"12angl ios idos is ' An 'J 'Hum'Genet " 30:3 lA

( 1 9 7 8 )

3. J . A . S i rnpson, D. A' Seaton, and J ' H ' Adaurs ' Response to t reatment

w i t h c h e l a t i n g a g e n t s o f a n e m i a ' c h r o n l c e n c e p h a l o p a t h y ' a n d m y e l o -pathy due to iu . i po ison ing, J 'Neuro l 'Neurosurg 'Psych ia t ry l

$iil

$$.r$

272536-541 1964)

4 . M. F i she r , J . E . M a t ee r , I ' U l l r i ch '

tract defic i ts an d polyneuropathy

cl in lcal ly nln lcking anyotrophic

7 .

an d J. A. Gutrecht, PYramJ'dal

in hyperthYroidism' Combination

l a t e r a l s c l e r o s l s , Am 'J 'M ed"

7 8 : 0 4 l - 1 0 4 4 ( 1 9 8 5 ) .

5. B. Pat tenr thosphate and parathyro id d isorders assoc ia ted wi th the

syndrome of "tyoitophi-c faterat sclerosis' ln:

t tHumanMotor Neuron

D i s e a s e s " , L . P . R o w l a n d , ed . , P p . 1 8 1 - 2 0 0 , i l - a v e nPress ' Ne w York

( 1 9 8 2 ) .

P. Stortebecker, Motor neuron disorder '

supply to spinal cord and brain-stem'

n e " e a i . t t , P p . 5 3 - 6 0 , S c o c k h o l n ( 1 9 8 3 ) '

if f ir ,r"ltop"atty-and motor neuron syndromes associated with

p lasma cel1 d isease, lc ia \e" ro . r 'qcu"4 "70247-61 (1984) Th is

reference is often nrrEEIGd-aE-Ttin[ in volume 59 of Acta Neurol'

6 .De f i c le n c Y o f ar ter ia l b lood

Foundat lon forStor tebecker

Scand. The cor rec t vo lume ls 70 '

8. H. A. Peters and D. V ' C la tanof f ' Sp ina l t " : :Y i i : a t rophy secondary to

rnacro lobu l inemia, Neuro logy ' i8 : 101-108 (1968) '

9 , B. par ren, ALS of aut6 f f iu ;E ; r ig in , Neuro logy , Suppl ' 1 ' 35:251

( 1 e 8 s ) .10. D. W. l Iu lder , ed. , "The Diagnos ls and Treatment of Amyot roph ic Latera l

Sclerosis", f iorrgtt tonMif i l in Professional Publishers' Medical

D iv is ion, Bos ton, MA (1980)

11. L . P. Rowland, ed ' ,t tHumanMotor Neuron Diseases ' Advances in

- -Nu, r ro logy t t , Vo1 ' 36, Raven Press ' New York (1982) - '

12 . F. C l i f f o rd-Rose ' ed ' ,t 'Research t iogress ln ] ' loEor Neuron Di -seaset "

Progress in t leuro logy Ser ies ' P i t ian ' Bath ' I JK ' (1984) '

13 . L. E. MaUette an d n' i l' pattenl Neurogenlc musclr lar-atrophy an d

osteomalacia in adult Fanconi syndr;ne' Ann'Neurol" l:13l-137

( 1 9 7 7 ) .

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The Syndromic Nature of ALS