ROUNDS II 191243 L. F. MYASTHENIA GRAV IS Parkland Memoria

ROUNDS
II 191243
MYASTHENIA GRAV IS
Parkland Memor i a l Hospli
November 16, 1961
L. F.
A 12 year old wh ite ma le who entered the hosp i tal w!th a two-month h i story of wa l ki ng
diff icult ies wi th sudden ta l Is and a waddl i ng ga lt • . He became progress i ve ly worse each day
bUt some days were better than othe r s. He was noted to walk on h i s toes and was unable to
'get up without help from a s itt i ng pos i t ion. A double bl i nd test wi th prost i gmin ' and
j8 trop i ne was done and he became perfectly resto r ed. A chest f il m i nd icated a mass i n the
' 8 nterior mediastinum but I year later the mass cou ld no longer be seen by the same x-ray
physic i an. l n the meant i me he had been contro l le d on prost i gm i n 22,5 + 22,5 + 15 mg/day.
fn August of 1961 he was sti I I on the same medication and pa r t i ci pated act i vely i n sports.
!
I
CASE I I.
II 072087
L.J.
This patient had the diagnos i s of MG made i n 1948 at the age of 33. She had treatment
, to r hyperthyroidism in 1949 with propylth iourac i l and Lugo l 1 s . l n !958 she had a total
~ thymectomy wh i ch reduced her need for med ication f rom 16-20 Mest i non per day to 4-5.
For
a four month period immed i ately after thymectomy she requ i r ed no med" c at ion. She had several
adm i ss ions after her thymectomy due to UR i. Her last adm is s ion was in J anuary of !961.
She developed a cold 8 hours PTA and f e lt weak and inc reased he r Mest i non i ntake to
an unknown number of tablets the last of which acco r d i ng to da ughter was take n 2 hours PTA.
She came i n i n severe respiratory distress, cyanot i c and gasp i ng for breath. After 40 mg
of Tens i len an i mprovement was noted but an add i t iona l 10 mg produ c ed cyanos i s and blood
pressu r e tel I to 80/50. She was intubated and suct ioned out and i mp roved somewhat. A new
Tens i !on i njection two hours later wi th 40 mg made the pat ient wake up but two mi nutes
later she was again i n severe anox i a and more Tens i !o n and an l .v. i nfus ion of 0,5 mg prost i gmi n ca lculated to go i n over one hou r was followed by apnea , The i .v. was aga i n d i scont i nued,
she was sucked out, was given Vand i d 100 mg wi th no ef f ect and aga i n Tensl !on at which stage
she woke up, started breath i ng on he r own, pu l led out the endotrachea l tube, sank back i nto
coma and suddenly d i ed.
!
CASE I I I.
II 188605
A.C.
I!
A 28 year old white female had onset of weakness at the age of 14. She was engaged
in competit ion sw i mming and f i rst not iced d i fficu lt i es l n gett i ng out of the sw i mming pool
i n sp i te of a good performance, The weakness prog r essed to i nvolve eye musc les and anter ior
t i bi al muscu lature and she went into cr i s i s after three years and requ ired resp i ratory care
and parentera l feed i ng. The d i agnos i s fo r four year s r ema i ned psychoneu ros i s and she was
di agnosed by the neurology consultant at the mental hosp i ta l t o wh ich she f i nally was
adm itted.
She was put on Mestinon afte r two years of prost i gm i ntherapy but fou nd this hard to
regulate and changed to Mytelase in 1954. She was radiated i n 1954 a nd 1956, the f i rst time
With temporary i mprovement, the second t i me wi th no i mprovement . When fi rst seen here In
1959 she was taking 30-35 Mytelase and 125 g of potass fum- cl t r ate pe r da y and re lat i vely
l ittle d i ff i culties with her myasthen i a. She had some outward de vi at ion of the left eye and
Was unable to cross her legs or stand on her heels. Only compl ic at ion of therapy was that
because she rece i ved free medicine the pharmac i st suspected her f o r us i ng the potassium
citrate as terti l i zer!
Chest x-ray was norma l and her thymus was removed i n 1959. On
operation the thym us was found to extend up under the i nfer ior pole of the thyro i d and giv i ng
a false i mpression of enlarged th yroi d. Path.: hyperplasia.
She needed no med i cat ion
fo r 5 days after the operation then had a couple of d i ff icu lt days wi th mi xed chol i ne r gi c
and myasthenic symptoms and sett led down on 1-l 1/2 tablets of Myte lase every 2 hou r s.
.I
lI
She has had 2 pregnancies :
The f i r st ch i d was st i I lbo r n and had muit i p le congen ital
-2-
obnormal i t i es. The second ch i ld was normal but died after 5 days in asp i ration, sudden
yanosis and apne.
No microscop i c abnormal ities found. She i s now aga i n pregnant.
Premenstrually and dur i ng the f i rst 4-5 months of her pregnanc i es she has exper ienced
of her clinical state, even after thymectomy. Dur in g the last tr imester she has had
marked improvement each time. She has had some unusual symptoms :
~orsening
1. She had on two occas ions unilateral pup i J lary d i latation wh ich was not changed by
medicat ion.
2. During each pregnancy she has had swell i ng of one o r more joints and has required
hydrocortisone.
3. She has had many episodes of severe substernal rad i at i ng chest pain.
4. She developed a general iz ed rash and a thyro i d ( thymus ?) swell i ng after a penici I linneosynephrine i njection.
She has posit i ve LE preparation, pos it i ve ant i nuc lear and negat ive latex f i xation test.
CASE lV.
# 206108
M.O.
Th i s 59 year old white female had a past hi sto ry of 2 years of occas ional general i zed
seizures and one Jacksonian seizure involving the r i ght leg. She also had mi ld diabetes and
was treated with Orinase and a blood pr essure of 190/l 10. She was adm i tted because of a
relatively sudden onset of garbled speech and double v i s ion i n the right eye together with
some facial weakness. She den i ed d i ff icult i es swallow i ng but descr i bed sudden attacks of
loss of consciousness and tal l i ng backwards. She had been work i ng as a wa i t r ess unti I 3 weeks
before admission when she became too qu ickly exhausted and could not cont i nue .
On admission she demonstrated weakness of left s i de of f ace, ptos i s, double v1s1on on
the right eye, and a th i ck speech which was hard to unde rs tand. The major di ff i culties involved the consonants. She had a Tens i Jon test wh i ch was not conv i nc i ng, but on repetit ion
a clear effect was obtained. She was started on Prost i gm i n. After 2 weeks a pos itive LE
preparat ion was obta i ned, her med i cation was stopped and 2 days late r a Tens i lon test was
repeated, this time double blind with calciumgluconate a control. It was cons i dered
negat i ve, however the testing was performed on the f i nger muscles wh i ch never had been involved. In order to investigate her se izure d i sorder a penumoencephalogram was done and
found normal.
On the night after the pneumoencephalogram the pat i ent became cyanotic and had great
difficult i es breathing. Intravenous Tens i Jon and Prosti gm i n intramuscularly restored her
completely and her speech became clear and i ntell i g i ble. She was placed on Mest i non and
atropin as needed and felt very well. Laminog r aphy of her chest revealed the presence of
[ faintly calcif i ed mult i lobulated dens ity i n the anteri o r med i ast i num. She was operated and a
thymoma was removed. The tumor i nvaded the pleu r a, the per i card i um and a branch of the
innom i nate vein. Follow i ng the ope r at ion she developed ma rked resp i rato r y di stress, cyanos i s
and apprehens ion. She was tested wi th Tensi lon, improved and wa s g i ven 0.25 mg Prost i gmin
intramuscularly. Shortly thereafter she aga i n became cyanotic and deve loped what was i nterpreted as pulmonary edema. She had a tracheostomy and was put on IPPB. Due to repeated
episodes of hypotension she also rece i ved cortisone. Two days later she exhibited marked ptos
and generalized weakness and was again tested with Tens i Jon . A ma r ked i mp rovement resulted an
an i .v. dr i p with 2,5 mg Prostigm i n/500 cc D5W was sta r ted. She rapidly became apne i c and had
to be started on control led resp i ration. Her uri na r y output started fall i ng and her BUN r i sin
She was found to have a pH of 6,97 and a pC0 2 of 120 mm. Gradua l restoration of normal values
- by the pulmonary service led to some clin i cal imp ro vement but her uri na r y output had fallen
In sp ite of i ncrease i n uri na r y output and ma i ntenance of blood pre
1 and her BUN reached 185.
sure with large quantit i es of levophed she exp ired o n the lOth postoperat i ve day.
-3-
DE F! NlTI ONS
Myasthen i a grav i s i s a chron ic di sease char.acter·i zed by weak ness an d abnormal
fat i gab i lit y of ske leta l mu scl e ( Grob 196 1) .
The s ymp tom s a r e commo nly amel iorated,
although to a va r i able degree by ant icho li nesterase compounds . Th·s r esponse serves
as the bas i s for d i agnos i s an d ma nagement o f the d i sease (Grob ) .
B. )
Any synd rome o f m~sc le wea kn es s not accompan i ed by alte r at ion o f tendo n reflexes i n
wh ich strength i mp r oves after the admi ni strat io n of adequate amounts of Pros t i gm i n or
Tens i /on should be cons i de red to be myasthenia gr av i s (Osser ma n).
c. )
Myasthen i a grav i s i s a s pec i f ic muscu la d i sease ch ar acter i zed by the deve lopment
of an abnorma l amoun t of muscu lar weakness i n volu ntary muscles foll ow i ng r epet i t i ve
act ion or pr olonged tens ion, wi th a mar ked tende nc y t o recovery of motor power after a
per iod of i nact i v i ty or less ened muscula r tens ion \ Vi ets ) .
GENE RA L REFERENCES
Myasthen i a Gr av i s.
Ar ch i v. of Inte r n. Med,
108: 4 (p. 6 15) Oct . 1961
I.
D. Grob .
2.
Vi ets, H. R., ed. 2nd Internat ional Sympos i um on Myasthen i a Grav i s.
Spr i ngf i e l d, 1961.
3.
Osserma n, K. E.
Myasthe ni a Gravis.
C. C. Thomas,
Grun e & Stratt on, No Y. 1958, 286 pp.
PATHOPHYSI OLOGY OF MYASTHENI A GRAVIS
A.)
Dimi ni shed acet ylchol i ne product ion o r r e le as e at ne rve end in gs.
4.
Harvey, A. M. and Masland, R. K.
A met hod fo r the study of neu romuscular transmission i n human s ub jects. Bu ll . Joh ns Hopk i ns Hosp. 68:81-93, 1941.
St imulat ion i s ap pl i ed percutaneously over the u ln a r nerve at the elbow;
record i ng from the ab ductor qigi t i qu int i with one e lectrode over the muscle belly
and one d i sta l ly ove r the muscl e te ndon; groun d i ng of patient at the wr i st.
5.
John, R. J ., Grob , D. and Harvey, A. MeG.
Stud i es in neuromus cular funct ion i I.
Bu I I. Johns Hopk ins Ho sp. 99 : 125- 135, 1956.
6.
Dah l b~ck,
0 ., Elmqu ist , D. , Johns , T. R., Rad ner , S. and Thesleff, s.
An electrophys iolog ic study of the neuromuscular j unct ion i n myast hen i a gr avi s.
J . Phys iol. London: 156 : 336-343, 1961.
Intercosta l muscl es from pati e nt s with myasthen i a gr av i s have normal res t i ng
potent i al, normal e nd plate potent i al. Mi ni at ure end p l ate ( m.e.p.p. ) were
abnormally few but of s i ze and t ime course as in norma l mu scle. Potass i um (30 mM)
de polarizat ion of the no r ma l musc le produces 1000- fo ld i nc r ease i n mi ni ature
potential freque ncy i n no r mal musc le ; no increase was seen i n myasthen ic muscle.
Cura rized no r ma l mu scle respond ed to tetanus with an inc rease in e nd p late pote ntia
non-cura r i zed myasthe nic muscl e wi th no post-tetan ic fac i li tat iono
Nachmansoh n has pointed out that the m.e. p.p. exi st even when t r ansmissio n is
blocked and offers no cl ue to state of endp l ate or te r minal ner ve fibers. The
tetanus effects cannot be comp ar e do The conclus·o n that t he def ect i n M.G" is i n
transm itter fo r mat io n o r re lease i s not ju st i f i ed.
- 4-
, B. )
Alte red morphology of neuromuscular junct ion .
7.
Lehrer, G. M.
Ultrastructure of iti e .manmal i an neuromuscul ar junct ion and the
local i zat ion of chol i nesterase .
2nd Interna l Myasthen i a Gr avis Sympos i um, 22-41,
1961 0
8.
MacDermot, V.
The changes i n the motor end p l ate i n myasthen i a gra vi s.
83 : 24-35, 1960.
9.
Bi ckerstaff, E. R. and Woo l f, A. L.
gravis. Bra i n: 83 : J0- 23, 1960.
C.)
Bra i n,
The i nt r amuscula r nerve end i ngs i n myasthen i a
Circulating curare like agent.
10.
Nowel 1, P. T. and Wi lson, A.
extracts of thymus glands .
Isolat ion o f quatern ary n itrogen compounds from
2nd Int. Symp. M. G. 1961, 238-257 .
Auto immune myos itis.
D.)
I I.
Teng, P. and Osserman, K. E.
Stud i es i n myasthen i a grav i s: Neo natal and j uven i /e
types. J . Mt. Si na i Hosp ital 23:711-727, 1956.
12.
Nastuk, W. L., Plescia, 0 . J . and Osserma n, K. E.
Changes i n serum complement
activ ity in pat i ents wi th myasthen i a grav i s. Proc . Soc. Exp. Bi oi. Med., 1960,
I 05, 177.
13.
Strauss, A. J. L., Seegal, B. c., Hs u, K. s. , Burkho lder, P. M., Nastuk, W. L. and
Osserman, K. E.
Prel i min ary observat io ns by immunof luorescence technique of a
muscle bi nding complement f ix i ng globu l i n i n the serums o f pat i ents wi th myas thenia grav i s. Proc. Soc. Exp. Bio L Med. 105:184, 1960 .
14.
Si mpson, J. A.
1960.
E.)
Myasthen i a Grav i s :
A new hypothes is .
Scott i sh Med. J. 2 : 419-436,
Endoct l ne changes _i n M. G.
15.
Schr i re, G.
Progesterone metabol ism i n myasthen i a gr av is.
109 : 59-75, 1959.
Qua r t. J . Med.
- 5-
PHARMACOLOGICAL TESTI NG OF MYASTHEN IA GRAV IS
A.)
Pat ie nts wi th suspect but not d i agnosed M. G.
Select muscle group wh ic h shows rap i d t i rin g on rep et it i ve act ion.
Give a double bl i nd test with atrop i ne as one of the substances 2 mg Tensi Jon I ,
If no react ion with i n 30 second s g ive add it io nal 8 mg .
If strong react ion with musc ar i n ic ef f ect t o 2 mg r epeat w·th .5 o r I mg after
I mg of atrop i n l .m.
Normal i nd ivi dua ls deve lop fasc icu lat io ns and mi nimal musc a ri nic reactions but
the effect is over with i n 5 minu tes.
Tens i ion can also be g ive n l. m. for test i ng: dose 10 mg.
effect 10 mi n.
Durat ion of
False posit i ve tests are usua l ly caught wit h double bl i nd technique.
If neost i gm i ne i s used instead of Tens i Jon t he recommended dose is 1-1,4 mg/100
lb bodywe i ght and .5-.7 mg atrop i ne/ 100 l b.
The effect i s noted after
10 mi nutes, reaches a maxi mum af ter 30 minutes but lasts for 3-4 hours.
Leav i ng out the at rop i ne has been fata l i n a few cases of nonmyasthenics.
I.V. neost i gm i n can be used but i s not genera l ly recommended .
Provocat ion tests : Qu i ni ne, d-tubocu r ar i ne and decamethon i um have been used
but neither should be tr i ed without the most carefu l supervision and the
two latter only with anesthes iolog i st present .
B.)
Testing of pat ients with known myasthen i a but with unknow n level of medication.
Best performed with i ntravenous tens i lon wi t hout atrop i ne g i ven. If patient's
resp i ratory state se~ms threatened, not more than 2 mg shoul d be given on
initial dose to be increased on ly if clear i mp ro vement foJ lows.
Occasional cases of the follow i ng d i seases have been noted to show sl i ght i mprovement
In symptomatology on Tens i Jon or neostigmine test i ng :
Amyotroph ic latera l sc le ros is
Po I i omye I I t i s
Progress i ve muscular at rop hy
Syr i ngomyel i a
Polymyos it i s
Carcinomatous myopathy
Multiple scleros is
Arter iosclerot ic cerebrovascula r d isease
See Reference 2.
-6MEDICATION
Pyr i dostigmine
Neostigmine
Prost i gm i
n~
Mest i non®
H C-
3
Acety I cho I i ne
0
- CI
- - - - - - - - - - Tens i Jon®
.
Amb enomtum, Mytefase
®
-7Add i tional drugs:
Ephedrine sulphate 25 mg b. i .d.
Atrop i ne 0.3-0.6 mg 1-3 t imes
Potassium chlor i de 2 g
Propant he li ne 15 mg
q. i. d.
a
day
q. i. d.
Drugs under tr i al :
Galantham i ne and Lycoram i ne
16.
Irwin, R. U. and Smith, M. J .
Chol i neste rase i nh i bit ion by galantham i ne and
lycoram i ne. Biochem. Pharmacol. ~ : 147-1 48, 1960.
Spirono lactone 100 mg q. i. d.
17.
Gott I i eb, B.
Lancet II :
and Laurent, L.P.E.
528- 529, 196 I.
Sp irono lacto ne i n the treatment of M. G.
Drugs wi th debatable effect:
ACTH,
cort i costero ids
and sex hormones.
Pa rot i d extracts.
Drugs to be avo i ded :
D-tubocurar i ne, Flaxed i I,
parenteral neomyc i n.
Myasthen i c cris i s :
succ i nylchol i ne,
qu i ni ne and qu ini d i ne,
Severe exacerbat io n of myasth en i a grav i s wi t h d if f i culty in
breat h i ng and swa l low i ng.
Management:
18.
Herrmann, C., Jr.
Cr i s i s i n myasthen i a grav i s.
Symp. 637-652, 1961.
Chol i nerg ic cr i sis :
Management :
19.
2n d Int . Myasthen i a Gravis
Paralysis of resp i r at ion and pha ryngea l muscu lature due to
excess ive dose of ant ichol i nesterase or the development of an
acetylchol i ne insens it i ve state.
See Her r man 's a rt icle and a lso
Osserman, K. E. and Genk i ns, G.
Med. Ql: 2076-2085, 1961.
St ud i es i n mya sthe n i a gr av i s .
N. Y. State J. of
THYMECTOMY
The procedure was i nt roduced by Sauerb r uch i n 1911 an d was or i g i nally used as an ope
at ion for hyperthy ro i d ism. The or i g i nal pat i ent had hyperthy roidis m and myasthen ia grav i s
the former remained unc hanged and the latter i mp r oved. Sauerbruch a lso operated the two
follow i ng cases, both of whom had thymomas and d i ed f rom med i ast i nit i s. From 1936 on the
development o f the operat ion ha s been ca r r ied on by Bl alock, Vi ets , Keynes, Clagett and
-"""
--·~---~ -~
~--
---·
-8-
Grob.
Most of the rev i ews of the resu lts are wr'tten by the med ·cal gi sts.
20.
An eva luai- ion of t hymectomy i n myasthen i a gr av i s. el:ll2-1 44,
S impson, J. A.
/958.
Rev iewin g 294 cases fro m Gr eat Br ita i n S. deci de d that i nd i vj f both
sexes with a du rat ion of the d i sease less than 5 years ber''3fi ted mil~ · rom
remova I o f thymus un Iess a thymoma wa s present. In the Iatte r case rognos i s
was poor a lthough ma rked i mprovement was somet imes seen.
21 .
Viets , H. R. and Schwab, R. A.
Thymectomy for myasthen i a gr avis. cpmas,
143 pp. 1960.
Us i ng matche d controls a se r ies of 100 no noperated and 10 1 o~cases the
improved cases amount to 61.% i n the operated aga i nst 21% i n the medtreated
with the mater i a l l i mited to females under 40. Ocu lar myasthenia se
excluded. Young ma les may do we i I a lthough ser i es is smal I. Other surgical
procedures are accompan ie d by exacerbat ions of the disease.
22.
Grob, D.
23.
Kree l , 1.,
Gen k i ns, G., Osserman, K. E. , J aco bson, E. and BaronofO.
Stu d ies i n myasthen i a grav i s : Improved t ech ni que s in thymectomy . J rg .
ill: 251-258, 1960.
24 .
Genk ins, G.
Techn i c a I care o f the thymectomy pati ent . Bu I I. N. Y. :ed .
36:826-829, 1960 .
Conta ins the best d irect io ns for pre and postoperat i ve ca r e .G.
pat i ent. St r esses par t icular ly the use of tracheostomy and mi nimapergic
drugs postoperat i vely.
25.
Bernatz , P. E., Harr i son, E. G. and Clagett, 0. T.
Th ymoma : A cl'hological study. J. Thorac. and Card iovasc . Surg . 42:424-441, 1961.
Myasthen i a Grav is. J . Chron. Dis • .§:536-566, 1958.
Grob takes a negative v i ew of the who le procedure. He uses as of M. G.
as control aga i nst the ope r ated and f i nds no change i n cour se of t nse
after operat ion.
MYASTHE NIC SYNDROMES
'
My~ sthen i a
grav i s and pos i t i ve L. E. pre parat ions.
26.
Hij mans, W. , Ki ev its, J . H. and Sch u it, R. H. E.
Di agnostic s i gn i ot
pos i t i ve L.E .-cel I phenomenon . Acta Med, Scand. 121:34 1-349, 1958
27 .
Harvey, A. M., Schulman, L. E.,
System i c lupus erythematosus.
28.
Denny, D. and Rose, R. L.
M. G. fol lowed by system ic Lupus erythe
Neurology _/_1 :71 0-713, 1961.
Tumu lt y, P. A., Conley, C. L. and ich , E. H.
Med ic i ne 33 : 291-437, 1954.
Myasthen i a grav i s and thy roi d disease.
Engel, A. G. Thyro i d funct·on and myasthen ic grav is , Arch . Neurol. 4, 1961
Myasthen ic syndrome with neoplasm.
30. Lambert, E. H., Rooke, E. D., Eaton, L and Hodson, C. H. Myasthen i 01e occas ionally assoc i ated with bronch i a l neoplasm . Myas t hen i a grav i s, ed s, N.Y.
1961, p. 362-410.
29.
-9 -
MYASTHEN IA CASES SEEN AT PARK LAND OR FO LLOWED JN CONSU LTATION 1951- 1961
emale
Numbe r
AgSl s;;Jt
onset
We I I, no
med ici ne
We I I,
med icat ion
7
12-59
0
4
12
14-58
6
ncaQac itated
Dead
l nsuff i c ient
data
0
2
2
9
Ni ne females had th ymectomies, th r ee with i n t he year of onset of the d isease,
fou r wi th i n 4 years and the other two 10 and 14 years a f te r onset :of Myasthen i a
One thymoma (Case IV) d i ed; a lI others had hyperplas i a of thymus or
symptomso
normal thymus o One o f the thymectom i es d i ed i n cr i s i s (Case I i); one had no
change i n med icat ion need or genera l status, and s ix had very marked i mp rovement.
ONSET OF THE DISEASE ACCORDING TO MUSC LE GROUP
Grob ( 1958 )
General i zed MoGo
300 caseso
Cases with ocular MoGo only exc!udedo
l
II
Park land Cases
Ptos i s
25
5/ 19
Diplop ia
24
1/19
Leg weakness
13
2/19
Blurred v i s io n
3
Genera I i zed fatigue
6
1/19
Di ff icu Jty l n swal low i ng
6
1/1 9
Di ff iculty i n speech
5
2/19
Di ff i cu lty i n chew i ng
4
0
Weakness i n arms
7:
...;
2/ 19
Weakness i n han ds
3
2/ 19
Weakness 1n neck
3
Weakness in f ace
3
Weakness i n trunk
Shortness of breath
0
0
1/ 19
2/19
0