LATERAL SCLEROSIS

TIIE SYNDROUIC NATT'REOF AMYOTROPHIC

B. M. Patten

Baylor CoLLegeof Medieine

Houston
Teaas, U.S.A

Introductlou

Let me start s'lth a confession' I do not,be11'Y"-::^::Yll'llll"ur"-

,.."'li'"li.iilii."';;r"
i:ii:?'":'fi';ilil""';"i'"-'a""";;;;: "s'a to
bother
:1"1Y?:::"1":i:ii.il""
r*
1:' .b":-":Y..i-::"::::::"t11"
i:,1"
qiil
.iil:"il:;';"""-"illii:il':1""1:':,
:iii:i":" :::,::*:;:'.::::i:ill"
fi:::lH.;H:';"i;;l;;:";i'd;;;:;l!;
ffii::fi:?-;;;;;;;nents
deluaEe
ietailed evaluatlon
:i :* 1f
andtheunusual
;:?ilil:"il"".'T;';-""-"a"""'"se
cau5c. ."
::u:i;.'::"':::"1:":'
:i":: :1'1:11",1"?.1?,i."
: :f :e^a^c;h- : - p; ;a-t:i ,e n t ,
o
,ue;1ys:
w itt h
w
1: ::':1::"T:"::
a clear
- - : e :il:tit:
conscl-en(
^ - ^ t s4 ^ ^
rhar I am not
^€ a \ r . . e s s - , - + ' c ocor-
n-
ilJ
wtitr.'""":lil::-"Tf::'1::::,::
$rt
expectation.of s\{ge9P'----d-
;;:ffi;.;;;-;;-;;;";-"nd
wastlng tlme oruoo"y wlih- reasonable
"rd ii the patlent'" :Sff
ductthe investisatl;"-;; ltl: 1"t:io:1-ll lii'lliil;":"lieach
l::::"fi;';"'..1-t"-.i";p'";-;; much rime and monev evaluatlng
i:':r::;
patlent with ALS as. I would have spent
if that patlent had ?cancer
l^A )nref

condition'
or
6 T
iI,I
leukernia or some otner usually serlous
and often fatal i.ril
a
ALS must be a syndrome and not
In this short Paper, I te11 why outline the current
prodt'"" the syndrone' I
disease and what titi"!" "a"paiients with tire ALS syndrone and lllustrate the
approach used to .."ii"tt with
c"st T h e - P a p e r c l o s e s
results of that approach wlth some " * t * p l e s ' of patients presenting with
evaluation
what I consider the-mlnimum standard
motor neuron dYsfunction'
the ALS situatlon never ceases to
The complexlty that encomPasses perslstence in followlng
io att"fi and dogged
amaze me. Constant ult""tio" into subgroups that can
break thls
up clues and abnormaiiii."--iri "yrrliot.
be studied and understood'

Why AIS must be a SYndrome

itself
of signs and symptorns' The word
A syndrome is a constellat{on when a grouP of signs
running tlgether' So
comes from the Greek meanlng a it means
and lower motor neuron signs
and syrnptoms run Eogether like "nl"t, syscem. ALs is no more a
or-ito"" p".t" Ll the nervous
there is failure
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 yofs f a i l t h e p a t rn
uremia. i e nthat
t
ana easity identified syndrome
shows characteristic merely diagnosing renal
himself in
case the doctor ao"" ,rot interlst He wants to find which one
failure. Instead'-i"-tt"t" to know the cause'
 of the causes of kidney fallure, among hundreds, is working in the patient
in question. And if he flnds a correctable problen, the specialist wlll
treat with a dogged tenacity to try to reverse the disease and solve the
patl"ent's problen.

rn the sanDeway, when motor neurons fail the patJ.ent shows character-
istic and easily ldentifled signs and symptoms of motor neuron dlsease, but
the physician should not be satisfied in making that discovery nor in
classlfying what notor neurons are not worklng. Our focus nust be on a
careful search for a cause of the motor neuron failure. rf we find a
treatable cause' we must treat wlth a dogged tenacity to reverse the
disease and to solve the patlentts problem. rt appears so obvlous there
are many causes of ALS that reviewlng the evidence seems trlvial. Never-
theless, I do review it here for purposes of exposition.

Brlef Su-ary of the Known Causes of the ALS Syndrone

There are several different types of lnherited AI-s including a sex

llnked and autosonnal dominant form so there must be different genes con-
trolling the expression of the condltionIl]. This nust automatically mean
there are several types of inherited ALS, each r^rith its own enzyme defic-
iency or structural cause. we know that hexosaminidase A deficiencv can
present with the signs of motor neuron disease with upper and lower moEor
neuron disease due to GM2ganglioside in the bodles of neurons[2]. This is
just one forn of the dlsease due to a metabolic leslon. I screened 56
consecutive patients before r found ny flrst case of Hex A deflciency
presenting as ALS. rnterestingly that patient had total Hex A deficiency
when tested with the artificial substrate, but was only 502 deflcient whln
t e s t e d w i t h t h e n a t u r a l G M 2g a n g l i o s i d e s u b s t r a t e , e x p l a i n i n g w h y h e h a d a n
ALS syndrone and not Tay-sachs dlsease. Lead poisonlng can produce ALS. A
detailed case report by sinpson published in 1966 proved that point[3].
simpsonrs patient, a welder with anemla, had excesslve excretion of lead ln
urine on EDTA wash out and made a complete recovery after deleading treat-
ment. That patlent remai.ns well 18 years after his disorder started
(personal conmunication, J. simpson). r have seen and treated several
si"milar cases. They are rare, but when found and treated they nay recover
amazingly well.

Hyperthyroidism can produce a picture like ALS in every way, except

the ALS goes away, in most cases when the hyperthyroidism stopsi4l. Hyper_
parathyroidism produces ALS which reverses in the early stages, if somlone
corrects the abnormalicy in calcium netabolisn[5]. cervical cord com-
pression and other diseases can sinulate ALS by causing upper and lower
motor neuron signs and syrnptons, a condition discussed in detail by
stortebecker[6]. soneti-nes, the patient has severe cervical and lumbar
spondylosis with multiple nerve root compressions giving fasclculations and
atrophy and other lower motor neuron signs in the lower extremities, a
sltuation i_llustrated below.

Recently, several authors have associated ALS with plasna cell disease
and monoclonal ganmopathy[7]. rntensive treatment of the monoclonal garDmo-
pathy can reverse or inprove the condition in some cases[g]. rf a rnono-
clonal gamnopathy can cause ALS, then llE_sust follow that a polyclonal
ganrcgathy can do Ehe same - an A.LS of 3aa1s
Detowlyl.

r00
 Current Approach to the Dlagnosls of ALS

L'LLNLCAL

Many papers and books cover the clinical diagnosl,s of ALS in

detail[10-12], but, I wonder how valuable the energy spent on detailed
history and physical examj.nation ls. The diagnosis is usually obvious fron
inspection and routlne examinatlon shows the characteristic signs of upper
and lower motor neuron dlsease with relative sparing of cerebellum, sensory
systens, and extraocular movement. The clinical flndlngs merely show that
the motor neurons are in trouble. Better to focus on finding the cause by
extenslve laboratory i-nvestigation. Nevertheless, some interesting
clinical features and their possible interpretation appear ln Table l.
Take these as rules of thumb which often work, but sometimes do not.

Laboratory

The laboratory tests j-mportant in investigating the ALS symdrome

appear in Table 2 with some comments about their significance. This is
what I consider the usual evaluatj.on, but again these are rules of churnb.
A conplete and detailed laboratory evaluation is more essential to the
understanding of ALS than any other nedical procedure lncluding history and
physical examinatlon. I lllustrate this point wlth the Een case examples
that follow.

L:r0ftD Le I

A 35 year o1d physiclan noted the gradual onset and continued pro-
:iiil
i;;J
gression of muscle weakness, atrophy, fasciculations, and cramps. 0n
examlnatlon, he had hyperreflexla, knee and ankle clonus, and severe weak-
ness of the proximal and distal muscles of upper and lower extremities
without sensory loss. He considered that he had ALS, buE refused further

Table 1. Clinical Clues that Suggest Atypical ALS

$.il
Iffi
'l.ril
Exposure to lead.
Long-term surviva].
Exacerbations and improvements.
Dry mouth and dry eyes and dry vagina (Sjogrenrs syndrone).
Skin rash parti-cularly over the elbows and knees and knuckles.
Renarkable worsening with exercj.se and improvement with rest.
;-\- Glove and sEocking sensory loss to pin and vibracion.
[' € R""o"iated other diseases of aucoinnune origin particularly severe insulin
dependent diabetes.
Dipiop ia.
Enlarged thyroid.
Lynphadenopathy.
Excessively rapid down-hill course.
Positi-ve tensilon test.
-
Poor range of motion of neck (may mean spondylosis).
- Ptosis (1ook for the ratrophic form of myasthenia gravisr).
- Excessive weight loss (suggests malabsorptlon and secondary hyperpara-
thyroidism). Sone patients rdith pancreatic insufficiency have been
nisdiagnosed as ALS. When there is the slightest doubt do the
appropriate tests to make sure that dlagnosls is ruled out.
\--. Diabetes urellitus especlally of recent onset. This ls often mistaken for
ALS and these patients have both diabetes and usually an autoimmune
inflamnatory neuropathy. They should be treated with Cytoxan if the
nerve biopsy shows vasculitis or inflannation.

l0l
 Table 2. Sunmary of Laboratory Items that should be done ln ALS

Blood tests
CBC, ESR, NaKCO2C1,SMA-15 (should include calcium and phosphate).
T3, T4, TSH and other thyrold tests.
Parathyroid hormone leve1.
Blood lead, mercury, alumlnum.
Rheunatoid factor, antinuclear antlbodj.es, compliment levels, serum
resol-ution a n d personallnspectlon of the
plate
p l a c e ttor monocLonal
or m onoc gamopaffifl
Hexosaminidase A and B.
Serum amino acld screen.
apr
Antiacetylcholine receptor antibody tlter.
Hepatitis screen for Hepatitis B surface antigen

Tissue biopsies
Muscle biopsy.
Sural nerve blopsy.
B1-opsies of mi"nor salivary glands if Sjogrenrs is suspected.

Other tests
Magnetic resonance of brain and spinal cord.
spinal tap with studies for er"ectrophoresis and oligoclonal bands.

E l - e c t r o m y o g r a ml o o k i n g for decrements with stimulation at 1ow (2 Hz) rates.

evaluatlon because he said he dld not fbelieve in doctors?. over a six

month perlod he declined so that he could no longer get up from a squat and
he had shortness of breath on walking across a room. Grip strength deter-
iorated fron 163 pounds to 80 pounds in fhe dominant right hand. A phys_
lcian friend drew thyroid tests when he saw how much excessive food the
patlent ate. The T4 was 23 and the thyroid scan diffusely overactive
establishj-ng the diagnosis of Graver" di""u.". The patient refused radio-
therapy, but took PTU with a return to euthyroidism, a 23 pound !/eight
gai-n, and an increase in grip to l12 pounds. The hyperreflexia and clonus
disappeared and he remains in rernission 9 years later.

Conrment: pyramidal tract deficits and polyneuropathy in hyper_

thyroidism in combination clinically mirnics ALS especially when the hyper-
thyroidism is long neglected as 1n the case here. i^/ith clrrection of the
hyperthyroidism, the nervous system probrems disappear in most cases[4].

Eronple 2

over three years a 4I year old man noted progressive weakness and
erasting of rnuscle and weight loss of l0 kilograms. on examlnation, he
could not lift legs against gravity nor stand alone without support.
Although al1 muscles were i-nvolved, proximal muscles were weaker than
distal and lower extremities were weaker Ehan upper extremities. There
were fasciculations in the atrophic muscles of the arms, but not ln the
tongue. Reflexes were hyperactive vrith knee and ankle clonus. A11 tests
of sensory, cerebellar, and cranlal nerve function gave normal results.
The clinical pi.cture was ALS, a diagnosis supporced by the finding of
severe neurogenic atrophy in the muscle biopsy. Because of complalnts of
joint pain, he appeared in the rheumatology clinic where his blood bicar-
:
t
'l

,'
LO2
bonate nas discovered to be slightly depressed to 19 meq/L. Further
revealed a Fanconl syndrome with aminoaciduria, phosphaturiar,,
evaluation
and uricouria. We admitted hin to the clinical research center and studied
him in detail to flnd that phosphate rePlacement alone corrected his
nervous system dlsease. As long as the phosphate continued, he renained
wel1. When the phosphate stopPed the ALS syndrome returned. Four years
later while stil1 taking replacement phosphate, he remains ellnically
normal and worklng ful1 tine.

coment: Dr. Mallette and I reported thls case in detail to Prove

ALS syn-
once and for all that a metabolic lesion can cause a reversible
'
drorne[13]

ExanPLe 3

A 55 year old neurosurgeon noted atrophy and weakness of his upper

extremltie; and fatigue while working. He examined hirnself and found
hyperreftexia and considered that he had ALS. 0n exaninatlon he had
and fasciculations of the extremitles, but the tongue was normal.
"iiopiry
ieflexes ltere hyperactive, but there was no babinski slgn' EMGwas not
fhe
angular dark fibers characteristic of
done, but muscle Ufopsy showed snall
n"rrrog"trl" atrophy. The sign out diagnosls agreed to by Ehe attending
ne'rologist (nyseit) and the residents was ALS. Three months later he
diplopia and was readrnitted. The tensilon test was positive and
developed

tiril
he had- antiacetylchollne recept.or antibodies ln his blood. Subsequently'
The
he was treated wlth nestinon, prednisone, cytoxan, and thymectomy'
diplopladlsappearedasdldhtsatrophyandhyperreflexia.Nowsevenyears
afier- the onset of his lllness he is without evidence of ALS.

tire
coilment: thls patient had an autolmune disease with
nyasthenia gravis .na u,s.
ALS synarome dlsappeared.
syndrome tf autoinmunl- orlgin.
with aggressive
Therefore,
treatment
the patient
The antiacetylchollne
a marker for the Presence of autoiunune mechanisrns in hj-s
of
features of
the myasthenla'
probably had an ALS
receptor antibody was
condition'
Iiil
i{:f
$:r.
Enonple 4
I$r
WG,a60yearoldmayorofasmallcityrdevelopedprogressiveweak- i.ril
with atrophy and fasciculations and
ness of upper ind lower extremities
There were bilateral bablnski signs and clonus. He was
hyperrefllxla.
wlth c1lnical examinations and EMG at the Mayo Cllnic and felt to
"u"t'.t"d
have ALS. When I saet hlm for a second opinlon, I agreed with the dlagnosis
The nuscle biopsy,
and did a muscle blopsy and spinal fluid examlnation.
blceps, showed severe neurogenlc atrophy' The spinal fluid was
frorn left
Later, he consulted another neurologist who dld a NMR scan of the
normal.
showed the lesions of urultiple sclerosis. RePeat spinal tap
brain which
bands. He r.tas tieated with three courses of l0 days
now showed oligoclonal
to walk. over
of ACTI{ a.nd cytoxan wlth improvement of strength and ability
the ensulng years hls improvement continues'

of subtle
Coxment: magnetic resonance imaging enables the detection
dlsease which eluded detection previously. There is
cases of white natter
sclerosls whlch ninics ALS as ill-ustrated by this
a form of multiple
patient.suspectthattypeofALSifthepatienthasanormaltongue,slow
scan, or oligoclonal
course, abnormal rdhite matter lesions on the magnetlc

i;.;jw":.:$l;'':l":i"ii.:::i.lll;'"]'i'i:::.::
oxldativestainofthemusclebiopsyindicatingthatinthiscasethe
rnultlple sclerosls was associated ltith peripheral nervous system dlsease
causing true muscle atroPhy'

103
 EronpLe 5

A 24 year old.wompn developed

severe progressive weakness of the
;::'ff:fiff.H'1,:;';fl:f";::,i31:'T.':.1:"^".;F-*;-;;";ue.(8rossa1
atrophy
as.having
oi.*."""*;,".,r.".
roi""r"li"Xi:,
*:ffi;:. iil..1;ff";";::jtrj:i:.
and conductlon velociri"" -r,ii""rJiroo",
neurogenlc atrophy, but obtatnabl".
the""r"'nol
spinal ir.ria showedsevere
cronar- ganmaglobulin. ,..t"i increase in pory_
Becausl oi-aii" "nor"a
day predni-sone. The inprover".ri-t""_r""" ti"ai"e-"hJ-iI] on alternate
disappearln* r"u "ru.a"d atrophy
"r"liig-rili rr.""",
bed to walking and:n:-r"ir"".lri";-;r*_inabilirv to sii up or rurn i.n
artendi.rg loffEg.. Recently, she gave blrth ro
normal infant' N-ot, 9 y"".i l"t"r'"h"-.orrti.rues a
with to dJ welr, although she
ur."i*i6'pJ,r,,a"
i.ip! ..,a roo. dropswhen
il"";;ii":"ak "-".Jiri-"lu
comment: peripheral.neuropathy
resenbles noror neuron can produce a clinlcal picture that
dlsease. u"a' air"
this patlenr had lirrl" r"t"i". "prr,.i
ii"ii"."."rned, r thoueht
*.ir,". p".ip;;;"i*Ioiai.io'
mistaken for notor neuron
disease is the i"".""t-;i";;;.
that can b!
patlent shows fasclculatlons There the
,,r".1" atrophy, i"i-"Ji"rry
Ereatment as is illustrated responds to
b "ra
y the ,ru*a
"""".
Euanple 6

A 52 year ord man devel0ped

muscle weakness and atrophy
generalized fasciculatlons. with severe
ir," F.""r"u1atlons i"'ir,"
especially on the rlght upper limbs
side. O n e x a m i n a t l o n , h ""r"
e f,ua-" .fgUa foot drop,
wastlng of hands, arms,
shoulders and proxlural muscles
Tendon reflexes were brisk oi arr" lower 1lmbs.
on the i"ito,t* bilateral
responses (positive e*i"rr"o. prantar
babinski slgns). He was ai"g"o""a-;J
trled on TRH and then cyclosporin n.rrirrg A_LSand
without benefit.
At age 55 when r saw hin ln
consultation r did spinar anesrhesla.
under complete sDinar anesthesla
arr"i".r"" no change in his severe
c u l a t l o n s , b u t t i r e E M Gd 1 d , r o t fasci_
inproved conslderably wlth or couprets. wrth Dilanti.n he
" t o r - i r i p r e t s
ro"" or ni" cramps and a return
in his abtrity
;:,:";:,1#"511;".lii":'T:::i::to''"-ina"*"nt
added "'"au"tio,,"o rhatthey
ro .i'" ..".i,"nr prosran.
was
"r.nri"lll":";:ii:":ll.tili;"ti3l!::l_"."
rated, refrexes becamebriJk agatn
,"a".,r"rop"a-iilrru". The Tegretol
disconrlnued and. rrro_other ag"ni"-1cror,"""p"r-1.,I
""J.n"
conplete control of hls ra"cic,rrrcion". oii"""r rrled rrirhour
of myellnated and unmyellnated A sural ,r"ru"-biop"y showedloss
fibers and some
biopsy showed neurogenic atrophy. The muscle
Blood ga"es "*or.t-"ii.rg"".
showed compensated res_
piratorv acldosls- He returned-to canada';;;"";;;=;t"r"'i"r"
syndrome was dlsputed-and,the of rssacsr
ai"g"o"i" of ALS reinstated.
mediclnes were altered and Later hls
he aetlriorated and died. ei-",raop"y (Dr H. v.
vinters' hrritten conmunlcation) there
was_no norphologic evidence
neuron disease in braln or of motor
spinal cord. There was i"".,rriars
brachial plexus and a severe of the
eoslnophilic "
nyocarditis.
coument: rssacsr can 100k like
dlagnosls the better part of
ALS. when there is a doubt about
the
*
va10r is to treat with Dilantln
Patient improves 1n strength as the fasclculati-orr" and see if the
under control. a.rJ-rrr"cle cramps come
Thls patient probably had a.rtoinmuneJl""u".
proiuclng p"'ipt'"ih- "n that was
nerve disease rhat resenbled the
;::::::'$"*:,:1

F
t
104
&
EnatQLe 7

A 22 year old mar: was first seen at age 14 complaining of progresslve

r:f the upper and lower extremities' He had been
weakness and atrophy
evaluated with muscle blopsy and EMGand felt
to have Progressive spinal
exceprE that the repetitive stlmulation studles showed
muscl-e atroPhy' He was
d""."t.rrt" lo low stinulus rates as are seen in myasthenla gravis'
Neurrcmuscular Disease conference at Baylor and felt to
nresented at the
r
f,;;;";;i;"i-.""""i", ,arrophy. Ar rhe time he was wheet chair bound.
Mestinon, and prednlsone on rhe theory he night have
ii""a"i hin with
gravj-s, but there tti to inprovement' Antiacetylcholine
ry"rat"oit
were not detected in hts blood' Subsequently' r
,l."paot
"rrlibodi"" and the Patient has undergone pro-
treated with cytoxan and thymectony
tte is now normal vlth no atrophy or weakness and
gressive improvement.
plays basketball etc.
but why? He
Comment: no questlon that thls patlent recovered,
of motor neuton dlsease associated with
protably had a courbination treat-
to lntensive and prolonged
iy."at"iri.. Both con.dltlons responded
nent.

EranPLe B
and weakness with signs
L 46 yeat o1d woman developed severe atrophy
of upper motor neurorr disease includlng
bablnski sign. Two rreurologlsts thougf,t
clonus'

biopsy"h"
had
hyperreflexla'

showed
ALS and so dld I'
neurogenic
and a

atrophy
She was
and
ri:ll
adnitted to the hospjltal where nuscle two week admission
sp:Lnal fluld,were Durlng the
the myelogram and "ott"i'-
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 llynphocytes'
with srnall
opsyofthese f'''
showed replacement of the nodal architecture a biopsy
tar I
eyes and dry-vagina,
Because she comprained of dry mouth and
of the lip minor glands was done
dry
ind showed lnflammation charac- 0t;
teristlc or s5ogren;,
".i1"".y
"y.rdionl".
she was treated wlth lntravenous cyEoxan
andmethylprednisoloinewithcornpleteremisslonofthelyraphadenopathy,
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 dpicture
of an ALS like
r o n e . S uwlth b s e -well
tlil
Tur
quently she has had two more occurrences wlthout Ehe
documented upper and lower motor neuron
she respondea
signs'
wittr
one
complete
with and one
remission of the f*ril
lyrnphadenopathy. Each tlme
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 br o
u tl o gs hl cea hl lays
she is now normal it."" y".." after Ehe start of her disease,
developed rheumatoid artirritis of the hands and her rheumatoid factor'
previouslY negative, i s Positive'

sinulating ALS' ['le have-

Comment: watch out for Sjogrenrs syndrome the cllnical
ary eyes and dry mouth,and
seen two other sj_mi1.ar cases ,tt to treatment'
that other F'hysicians called ALS' A11 responded
pi"irrt"
are indicated ln any ALS patient
A tear test and the rlse bengal test then the patlent
If those tests are posltlve'
who complains of dr1' eyes' of
gland biopsy to prove the.diagnosis
should get a mlnor-i,"fit't'y condition'
j-ntensive treatrnenc of the autolmmune
Sjogrenrs followed try

ExanPLe 9
in the hands followed by atrophy
At age 53 this ttoman noted weakness
Withtn six rnonths' both lower
and weakness of ti" upper extremitles' fasciculations'
were also involved with atrophy, weakness,_and
extremities
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 , sjaw
w a l ljerk,
o w l n g atroPhy'
' a n d t a l k i nweakness
g.
hyperactive
on examlnatrorr, .i'-ug"-54 sire had a and fascl-
of the tongue, t".L"a atrophy, weakness
and fasciculatlons with clonus'
and lowlr extrenitles
culations of the museles of the upper unable to ro11
bibinskl slgns. she was
crossed adductors and bilateral

105
 over i'n bed, much less sit, stand or wa1k. There were Do sensory, cer-
ebellar or sphincter abnormalities.

B100d and csF showed a monoclonal gannopathy

of the rGG kappa type.
we treated her intensively with 15 plasna exchanges, daily cytoxan and
prednisone with no change in her conditiorr. treltment was abandoned after
she became leucopenic.

conment: this is not the first case of ALS associated wlth a nono-
clonal gannopathy that,falled to respond to treatment. Some patients do
not respond, but some do as is illuslrated by the next case[g].
Eranrple 10

At age 57 this woman noted difficulty in swallowlng, forrowed by

trouble walking. within one year, she 10st 35 pounds, Irra ir"a difficulty
clinbing stalrs, getting out of a chair, and bathing. she compralned of a
poor appetite and a peculi.ar metallic taste in her mouth. on examination
at age 58' she showed severe atrophy and weakness
of the muscles of upper
and lower extremiries with some dysphagia but otherwi-se normal crani.al
nerves. Deep tendon reflexes were normal, and there
were no cerebellar,
sensory' or sphlncter disturbances. Her father di-ed of leukenia and her
mother dled of cancer of the colon.

Brood work showed a monoclonal rGG of kappa type

and she had diffuse
osteoporosis of the vertebral column. Muscle bropsy showed moderate neuro_
genic atrophy. She got worse and became so weak she could not lift
her
Iegs against gravity. The reflexes became hyperactlve !r'ith abnornal spread
thus givlng the clinlcal appearance of ALS. A bone marro' showed greater
than 52 plasma cel1s so she was started on a program of
vincri.stin,
Melphalan, and prednlsone because it appeared thit
her ALS was headed for a
fatal terninatlon. Her reflexes becane hypoactive, but her strength and
muscre bulk dramatically improved so that she was now able to holJ her regs
agai'nst gravlty for over 40 seconds, and she could
c11nb stalrs, get out of
a chair, do her hair, get up from a squat, and swallow
normally. The
strange abnormal taste in her mouth di,sappeared. over the course of three
months, she gained about 20 pounds in weight and returned
to work. The
concentration of M proteln in her serum was reduced to about
502 of its
lnitlal value. she continued to do well for about four months until
she
agaln noted increasing weakness and fati-gue. This time she was treated
with intravenous cyroxan (750 mg each, total dose = 1500 ng)
and 5 plasma
exchanges of 2 liters each. coincident with this treatment there was a
greater than 502 reductlon in the seruu level of the
monoclonal protein, a
two fold increase in grip strength, and a 592 i.ncrease ln reg hoidirrg tine
and a return of her head holding tine to normal (greater
than 60 secJnds).
she dld well for another 5 months and then developed a cancer
of the 1ung.
she died of Ehat disease wi.ch a recurrence of the Ar,s llke picture.

comment: she is not the flrst patlent with the ALS syndrome associated
with a monoclonal protein to respond to treatnent[g]. She probably had a
paraneoplastic syndrome wi.th the monocl0nal protein a response to the
presence of an occult cancer of the lung.

Concluslons

ALS is not a disease. It is a syndrome suggesting the patient has

dysfunction of the lower and upper motor tte.trotti. we know in rare
instances that this syndrome can be caused by cervical spondylosis, heavy
metal intoxicatlon, by hexosLninidase deficiency, and by plasma cell
dlsease. An autoinmune form of Al,S probably also exists.-

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 WeshouldstudyeachAJ,spatientwithnultlplebloodtestsandoerve from
nay beneflt
and nuscle biopsles in the hopls of picklng up the few who
energy and rnoney evalu-
treatment. My motto ls to spend as much tlme and
had leukenia or
atlng an ALS patlent as we would have spent if that patlent
lor"-ott.. serlous and usually fatal disorder'

ALS has significant.autoilmune dlsease'

If a patient nlth clinical Hopefully,
not trlat them inteoslvely.
then I see no reason that we should serious abnorm-
or remit' If we discover any oEher
the ALS wiII inprove
alltyduringdetailedevaluation'weshouldtreatltwlthadoggedtenacity
ln the hoPe the ALS night lmProve'

Acknowledgeoent
from The George and lrene Lindler
This work was suPPorted by gifts
Foundatlon and a gift from Bruce and Burlene Bauman'

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