HYPERKALEM
IC FAMILIAL
PERIODIC
PARALYSIS
T. J. Egan, M.D.C.M., and R. Klein, M.D.
l)epartnient
of
Pediatrics, University of Pittshurglm School of Medicine, and Children’s Hospital of PittsburghGenetics
As previously reported!, the disease is
hiere(!itary alid due to a single autosomal
(Accepted May 21, 1959; stmbmiiitted January 7.)
Studies supported in part I)y the National Institutes of Health (Grant A-i 10:3 C), Public Health Service ,tIi(l by the Anierican Camicer Society (Grant e-EDC45A t).
ADDRESS: (IlK.) Childremi’s Ilospital, 125 I)eSoto Street, Pittsbtmrghi 13, Pennsylvania.
PmcmAlnIcs, Noe:u,her 1 9.59
761
H
EREDITA1IY periodic paralysis has beenrecogllized as a clinical entity since
tue first case report appeared in 1882.’ The lileciianism of attacks in this disease remains
obscure. Observation has been made in a
miumllii)er of sttic!ies that a diminution in
con-centration of 1)t1S5iuIil in the serum
ac-coulipamlies paralytic seizures2’ and iii later years more definitive studies have confirmed
this fact. Ill 1957, Gamstrop et (ii.’
re-1)orte! t\V() families who stmffered from a
dis-ease clinically resembling familial periodic
paralysis i)ut characterized by elevated
con-centrations of potassitum in the serum during
the paralytic attacks. It is probable that
the several reports” appearing in the
liter-atumre describing patients with familial
pen-odic paralysis \Vh() do not demonstrate a fall
in concentration of potassium with paralytic
episodes or \Vil() have been refractory to the
oral administration of potassium salts,
rep-resent examples of this syndrome.
PATIENT
MATERIAL
\Ve have studied tile members of three umi-related families who suffer from the hyperka-iemic variant of familial periodic paralysis. Clinical histories relating to attacks were ob-taimied directly from eleven affected persomis amid indirectly on 30 others through informatioi supplied by close relatives. The ages of affected imidividuals ramiged from 19 months to 65 ears. Five affected persons were selected fromii the three famnihics to be hospitalized amid stumdied
iii detail.
OBSERVATIONS
d!omrnant with almost conii)lete penetrance
(
Figs. 1-3). The only instance of incompletepenetrance appears in the Kr family. It will
be noted that one boy in this family whose
great-grandfather was sYiiiptoniat:c an(l
whose grandfather and father had been
symptom-free. had begun to have attacks
(Fig. 1). In tv() of the three families there
was a history of dhabetes alid, ili(!eed,
member of the Sp family was affected by
1)0th diseases. Twenty-three of tue affected!
members were males and 18 were females.
The three families had diverse national
on-gins including Italy, Ireland and the
Nether-lands.
Symptoms and Signs
Onset of symptoms usually occurred!
he-tween 2 and 3 years of age. In mnost cases
symptoms were apparent siiortly after
af-fected ciiildren had learned to walk veii,
which suggests that symptoms may have
been present earlier but were masked by
the expected instability of gait at an earlier
age. The paralytic attacks varied in both
freqtlency and intensity in affected sibs. Ill
general, attacks became less frequent btmt
more prolonged and severe with increasing
age. The frequency of attacks varied from
four to five times a week to once a month.
Attacks never occurred during exercise.
They were most frequently precipitated by
rest after physical exertion, by fasting, or by
exposure to cold or damp weather. As might
be expected, episodes were more frequent
diuning the winter than the summer. Attacks
most frequently occurred in the evening
after rest or in the morning before arising,
x
MEMBERS AFFECTED
X MEMBERS STUDIED
miormiial sleepimig period and thuis delayed ingestu)n of the niorning lileal. Nienibers of
t\V() of the faniiiies regum!arlv attelld!edl chnircli services in tue fasting state and in-Varial)lv 5ul!fd’re(l from attacks of weakness (lumring the church services. Affected school
x
.
.
Memb.rsx
M.mbers StudiedlI(. 2. lk(higr(( of Kt ha,uuilv. Svmiihols as in Figure 1. Arro imi(licates ptti(mit stuclie(l imi
another hospital as (lescril)ed in t(xt.
Fic. 1. lkdigree of Kr Fammmily. \Iales imidicated l)v squares, femiiales by circles. Affected niemiuhers iii-(Ii(Lt((l Ii’ solid svnmbols. X in(licates imidivi(ltmals stuclicul imi the hiOsI)ital.
chiik!remi had almiiost daily attacks diunilig
the niornmg school session and! these
oc-curred most frequientl if they had! walked to sciiool on a coldl day before sitting in a warm classroom.
DIEDIN NEONATAL PERIOD
9X
_____
11o1
lobe
4
R
#{149}
MEMBERS AFFECTEDx MEMBERS STUDIED
Imc. 3. Pedigree of Sp Faniily. Syllibols as imi Figtmrc 1. The niale infamit who (lied ii the neonatal prioi (I(1)i(t((I 1)11 tIn extremmie I(ft was the twimi of affected male vhio was studied imi the hospital. The type
of tvimimiing COuld1 not be identified.
faniilies reported increasimig seventy of
at-tacks duiring the last two tnimesters of
preg-miauicv. These severe attacks did not ternli-miite vithi delivery but couitiuiumed with
dc-creasing seven tv d!tmniuig the l)tlerPenitmmii. This fimiding has i)een observed in an earlier report of a famiiily vitii hereditary paralysis
refractory to oral a(Imilmnistratmon of
I)Otas-SiUlil. I)ne affected niotlier had i)eem1 free of
attacks from adolescence until
approxi-IiiatelV the fourth milolithi of lien first
preg-nancy.
Camiistorji (‘t al.’ re1)orted that attacks
COuld! i)e i)recipititedl in aff(cted1 ilid!ividltlals
l)y the oral nigestion of 1.0 to 2.5 gin of
1)tiSsiummii. \Vhile obtaining a clinical history of IiidITll)ers of the Kt family, we were
stir-iiris’! to learn that tue imigestion of
canta-loupe h’ affected miiemiibers of the family
seemiie(! to prcipitmtte paralytic episo(!es. Reference to a standlardi (hetarv Inaiiual
re-vealer! that the aerage hospital serving of
cm-tmitalon P
(
imiiately 200 granis ofe(lible fruit) contains 0.46 graIns of potas-silmlii.’2 \\-Thien the effect of cantalotupe
in-gestion \‘as reported to the Kr family, the
fruit as constmnied and an episode of rnums-dIe weakness eliSIle(l iii affected mnenil)ers of
tIme famnily.
Amiestliesia LI)1)ears to l)r(cil)itate se’ere
1)t1al’sis. Each of the three faniihies has at least one affected meml)er who has received!
an allestiietic either for the PtmrP5e of dental extractions or childbirth. In emuchi ilistauice,
cli awakening from anesthesia, the I)atiellt
was unal)le to move for from 2 to 5 hours.
The anesthetic aIm inisteredl for dk’Iita!
)r-cedures was pentothal sodium. The general
anesthetic given for childbirth has not Iwcii identified!. One patient delivered a chiild
hater with spinal anesthesia without
sums-tabling an attack.
The extent of involvement was variable
ill tue same patient cii each occasion.
In-‘olved most frequmently were the lower
hrnl)s, and with decreasing freqtmencv, the
upper limbs, the trullik IiilIscleS, and the facial muscles includ!ing those of die tongume
and! the eyelids. Two of the families
re-ported episodles of sI)asm of facial mtiscles and! difficulty in articulation duniiig attacks
1)reciPitttte! liv exposuure of the face and
hidlid!5 to cOld Ol dampness. The attacks as
reported and as oI)served by us in hospital were frequently asynillietnical in severity, one leg or OliC arm heimig niore affectedi than the other. The miiuscles of respiration have never been affectedi in any of our patients.
Both ill adumlts alid! in ciiildren we
oh-served tue onset of attacks to be associatedi vith i definite uIieasiIiesS and fear vhiic1i
q)peared to 1e d!isproportiomhute t() tl1(’
actual physical disconifort of the 1)atients.
ob-764
servation as 1)eculiar to their attacks at
home as well as those observed in hospital.
The attacks are preceded by an aura
con-sisting of a feeling of heaviness in the limbs
and described as “cramps” by two of the
families even though there is never
associ-ated pain. Affected persons can often ward
off an attack at this point by gentle exercise
of the affected muscles. However, if the
attack once proceeds past this point, they
find themselves unable to move the affected
limbs. Two patients in the present series are
unable to stlpl)ort their heads at the height
of an attack. Two patients are unable to
raise the upper eyelids dinning these
epi-soles and four patients report that on
cc-casion they have been tunable to speak
in-telhigibl.
The dumration of attacks is variable,
rang-ing from a few minutes to several hours.
Re-covery from severe attacks is frequently
followed! by )rolonged aching of the
mus-des of the limbs which may last as long as
a week.
Affected individumals felt vehl between
at-tacks. Two patients reported thiey hadi noted
fibrillation of muscles on occason during
attack-free periods. A few of the affected
members hadi from time to time been
ac-cumsedl
by
vell-meanng physicians orem-plovers of malingeni:ig and one patient had
been referred for pscliiatnic care. All mem-i)ens of the three families were aware of the
familial nature of the disease but had
ad-justed well to thie affliction, perhaps aided
by the knowledge that none of their
ances-tons had been reported to have died from
the maladiy. Affectedi persons in the Kt
famnily had been given potassium chlonidle
orally iy a )hysician at one time btit
they had discontinumedi the medication
theni-selves, recognizing that it had no effect in
ameliorating their symptoms. One member
of this family (designated by an arrow in
Fig. 2) had been admitted to hospital for
study while free of symptoms at the age of
17 years, suspected of iiypokalemic familial
Ileniodlic I)ctnalysis. She received insulill and glucose i)y continuous infusion for a period
of approximately 60 hours. Although the
concentration of potassium in the serum fell
to 3 meq!l during the infusion, no cbnical
evidence of paresis ensued, and repeated
muscle testing failed to demonstrate
weak-ness.13
Members of the three families reported
the ingestion of high carbohydrate snacks
between meals, although only one of these
families had recognized that this action
seemed to lessen the frequiency and severity of attacks.
Physical and neurologic examination in
symptom-free patients was not remarkable.
One patient in the Kr family and several
members of the Sp family were noted to be
umnusually muscular in build. This finding had been reported by others.11
ProceJures
METABOLIC
STUDIES
\letabolc studiies were performed on t\V7)
miiembers of the Kr family, one member of
the Kt family, two members of the Sp family
amid suitable control stibjects. The subjects were
given a feeding high ill carbohydrate cmi the
evening before each study and nothing b’
mouth thereafter save sufficient water to
re-place uriliary losses. Control spccimnemis of
urine amid blood were obtained in the miiornimig before and after a period of 1 hour of enforced
activity. At the end of this hour the patient was
again put to bed and las’ quietly, interrupted
only by the periodic collection of specimemis of
blood and urine. This regimen was comitinued
tlfltii paralytic symptoms and signs were
evi-dent in most cases.
Samples of venous i)lood were obtained from
the antectmbital vein in heparinized syringes
amid dlehivere(i into heparinized test tubes tmmider
oil. Iii the niajonity of studies, arteniahized cpi1-larv blood! was obtained!, as nearly simnultamie-mushy as possible with the venous sample, from the warmed finger tips of the same extremity. In a single study (Fig. 4 and Table I, Expeni-ment 3) blood ws obtained simultaneously from the brachial artery amid antecubital vein through imidwelling polveth1emie catheters.
Studies Performed
S.0
ARTICLES
765
- 5.0
a.
E .<
‘I,
.(
_1
z
TI#{128}IN MINUTES
.--- --0 VENOUS
(I,
z
0
.(
I-z w
U
z
-0
Uz
E
.- . ATLIAL
IIllllDIllllhIl
CLINICALLY D(TECTAIL[ WEAKNESSImc. 4. Comicentratiomis of sodimmni ammdpotissitmmii iii arterial ami(! emioims
plasmIla of: 7-year-old bo (patient llKr) before, during, timid after a
spt)mit1tmi()tms attack of paralysis.
The I)11t1(mlt W1IS anhl)tmlatorv for the first 50 minumtcs. Immiiediatcly after the secomid samples of blood were OI)tailied he lay (lowmi amid rc-mnaimue(! supine for the rest of the test. The third samples of blood were Obtaifle(! 10 mmiimiumtes after the assummiiptioli of the supine position and
preccde(! ol)vioums paralysis h 15 niinuites.
miia(le imi all bumt Experimiiemits 1 ami! 9, iii which arterial or capillary specimnens were not ob-tune(! . Comicentrations of total proteimi , calcium,
phosphorus, carbon dioxide comitent amid pH imi
l)llsma of venous blood! were determined imi
fromii three to six studies. The comicemitration of niagnesiummul ill serumn was deternii,iec! imit\V() of the studies. Specimens of urine were collected (!urimig sevemi studies at the time of sampling of 1)100(1 whiemiever it was possible for the subject to void. Rates of excretion were calculated for water, 50(hitllii, potassiummii, amid phosphorus.
The effects of the administration of glucagon (30 i.g -kg) imitraveliously, epinephnine (0.25 to 0.4 ml of a 1:1,000 diluition of epinephrimie hv(lrochloride) subcutaneously, glucose (1.75
gill kg) orally, and calcitim gluconate (10 ml
of a 10% soluition) intravenously during a clini-cal attack were observed.
The comitrol subjects were selected from nor-mual children on the medical or surgical wards of the hospital. They were treated km the same
mnanmier as the I)ttie1its amid collections of urine amid l)lood were made under identical
condi-tiolis.
Serial electrocardiograms were performed during a iiumber of stumdies.
Electroencephalo-grams were performed on patients RKr amid
JSp, Jr. The latter study was repeated after 2
days of therapy with dextro-amphetaminc
sul-fate.
Methods
Concentrations of sodium amid potassium iii
plasma and urine were determined using a
flame photometer with an internal hithiuni
standard. The error iii the method is
approxi-mately 1%. The content of carbon dioxide iii plasma was determined usimig the Van
Slyke-Neill manometnic apparatus.’4 Plasma pH was
determined on a Model C Beckman pH meter
at room temperature and corrected to 37#{176}C.
The concemitration of sugar was determined
TABLE I
ELECTROLYTES AND PROTEIN IN PLASMA IN PATIENTS WITH HYPERKALEMIC PERIODIC PARALYSIS
Patient
s
Age
Exp. No.
Period
Concentrations in Plasma
Total
Proteins (gm/1 ml)
venous K
(meq/l) capillary venous
Na (meq/l) capillary venous
P
(mg/ ml) venous
RKrMaIe7yr 1 Attack 5.3 150 6.5 7.
Attack 7.5 7.0 4O 141 &.6 7.6
Therapy Glucagon, SO mg/kg intravenously
Post-attack
<30mm 5.8 5.0 145 145 4.1 7.9
>30mm 6.0 5.0 144 141 .5.1
S Pre-attack 5.0 4.7 141 139 5.4 6.9
Early attack .5.2 4 .7 148 148 5 .3 7.
Lateattack 5.0 4.6 143 139 5.3 6.6
Post-attack
<30mm 5.1 4.5 139 138 4.9 6.9
>30mm 4.0 4.7 139 143 4.5 6.5
4 Pre-attack 5.4 6. 135 131 5.6
Attack 5.5 4.6 137 13 5.2 8.4
Therapy Epinephrine 1 : 1 ,000, O.Q5 ml subcutaneously
Post-attack
<80mm 8.4 3.0 186 19 5.8 7.4 >80mm 4.1 3.6 137 138 6.3 6.6
MKr Female 3yr 5 Pre-attack 4.9 4.4 129 137 3.6 7.1
(7 months pregnant) Attack 6. 4 .5 16 184 3.9 6.6
Therapy Calcium gluconate 1O%-1O ml intravenously
Post-attack
<30 mm
>sOmmn 5.3 4.7 134 133 3.5 7.1
RKt Male 14 yr 6 Pre-attack 5.1 4.6 188 141 5. 5.8
Earlyattack 5.6 5.7 189 153 5. 6.4
Lateattack 6.0 5.5 185 187 4.6 6.9
Therapy Epinephrine I : 1,000, 0.3 ml subcutaneously
Post-attack
<3Ommn 4.6 4.5 136 139 3.8
>30mm 4.9 4.6 187 143 4.0 6.8
J.Sp., Jr. Male 8 yr 7 Pre-attack 5.1 4.9 14 143
Therapy Glucose, 1.75 gm/kg orally
Earlyattack 5.6 6.0 143 141
Lateattack 5.7 6. 141 144
Post-attack
<30mm 5.0 5.8 14 14
>30mm 4.7 5.0 14 143
ARTICLES
767TABLE I (Continued)
Patient
Sex
Age
l’Xj).
.\o. Period
Concentrations in Plasma
-P Total
K Na
(rng/ Proteins
(meq/l) (meq/l)
100 ml) (gin/I00 rot) capillary venous capillary venous
venous venous
8* Pre-attack 4.3 3.9 142 140 7.2 Earlyatt.ack 4.5 4.7 141 142
Late attack 5.0 4.7 137 144 6.7
Therapy Dextro-amphetamine, 10 mg intramuscularly
Post-attack
<30mm 4.8 4.8 140 144 6.8 >30mm 4.6 4.5 142 140 6.3
ISp., Sr. Male 9* Pre-attack 4.6 140 6.5
30 yr Early attack
Late attack Therapy
Post-attack <30mm
5.6 140 6.5
5.1 140 6.2
Dextro-amphetamine, 15 tug intramuscularly
4.3 141 6.0
S 1mmExperimmients 8 and 9, the patients had subjective symptoms of an attack but paresis could not be
demnomm-strated.
calcium was measured by a modiflcationle of
the method of Tisdall and that of phosphorus
according to Fiske and SubbaRow.17
Concentra-tion of total protein in serum was determined
using the Reinhold modificationhs of the biuret
method. Determinations of concentration of
magnesium were performed by the Bio-Science Laboratories. #{176}
OBSERVATIONS
DURING
PARALYTIC
A1TACKS
By the method described, paralytic
epi-sodes were witnessed in four patients on 7
of 9 occasions. Since the legs were
consist-ently affected, inability to raise the legs
from the bed was the objective criterion
for diagnosis of paresis.
In
the
remaining
two experiments, the patients developed
symptoms which they had come to associate
with attacks, but they were able to raise
the legs from the bed. Attacks usually
oc-curred 30 to 90 minutes after the patient
had returned to bed. The onset of attacks
was signaled by a sensation of numbness in
the affected areas of the body and
pro-gressed to paresis, as has been previously
0 2231 S. Carmelina Avenue, Los Angeles 64,
California.
described. The deep tendon reflexes were
unaltered during the period of paresis. Serial electrocardiograms demonstrated
alteration of the configuration of the T
wave with increased amplitude and
peak-ing, which appeared to be maximal before
evidence of paresis was observed. The
ad-ministration of glucagon or epinephrine led
to a marked reduction of the size of the T
wave and the production of a U wave which
correlated with the fall in concentration of
potassium in the plasma and the
disappear-ance of paretic signs (Fig.
5).
Electroencephalograms of both patients
revealed bilateral bursts of high amplitude,
slow activity, and hyperventilation
pro-duced disorganization with much slowing.
The electroencephalographic tracing on
pa-tient JSp, Jr., after 2 days of therapy with
dextroamphetamine sulfate, showed
consid-erable improvement over the previous
rec-ord (Fig. 6).
RESULTS
OF
METABOLIC
STUDIES
Concentrations of potassium, sodium,
phosphorus and total protein in the plasma
pre-BEFORE DURING 30 MINUTES 60 MINUTES
ATTACK ATTACK AFTER DRUG AFTER DRUG
PATIENT
RKN (CAD1KG V4
PLASMA CAPILLARY
K
MIQ I.. VCPIOUS
J4
5.4
6.
5.5 4S
EPINEPHRINE
3.4 3 0
j
3.4 3.3
WEs V4
CONTROLPATIENT LtAD(KG
PLASMA CAPILLARY
K
M( L. V(HOUS
5.2 4.2
EPINEPHRINE
JrA.J1_
4.9
3.5
4.1
3.5
PAT(NT
R KR LEAD(KG
VA
PLASMA CAPILLARY
K
MEG. L. V(NOUS
k#s._.k#_.
7.5 7 0
GLUCAGON
.-+-.---,--..
5.6
5.0
.1”%-_.__#.Sr”-%.
6.0
4.4
CONTROL (KG
PATIENT L(AD JVi VA
PLASMA CAPILLARY
K
M(Q. L. V(NOUS
J
4.7
4.2
I
0LUCAGON
4.1
4.2
4.4 4.0
FIG. 5. Tracings of electrocardiograms (lead V4) in patients with hyperkalemic familial periodic paralysis before and during spontaneous attacks of paralysis and after disappearance of symptoms following
miiedication.
As controls, electrocardiograms from normal children 1)efore and after the same medications are de-picted. Concentrations of potassium in plasma, meastmred at times of electrocardiograms, are given below
the drawings.
TABLE II
MEAN CONCENTRATIONS OF POTASSIUM, SODIUM AND PHosPuoRUs IN PATiENTS WITh
HYPERKALEMIC PERIODIC PARALYSIS AND IN CONTROL SUBJE#{128}rS
Period
Cone entrations in Plasma
(
arterial K meq/l)
venous
Na (meq/l) arterial venous
P (mg/100 ml)
m’enous
Pre-attack 5.0 4.6 139 140 5.0
Patients Attack 5.6 5.3 139 142 5.2
Post-attack 4.9 4.5 139 139 4.8 Control 4.8 4.5 139 139 5.1
Normal subjects After glucagon or
epimmephrine 4.6 4.4 139 140 4.5
BEFORE
THERAPY
\AJ\J4v4JAwv4jv
Vv\/v\J&\J\JAv\ILf\,\r\f\
.
AFTER
cI-.AMPHETAMWIE
‘‘
-,‘--,,.--
,‘-_,__
w-FIG. 6. Standard-lead electroencephalogranis of an 8-year-old boy with hyperkalemic periodic paralysis during asymriptomiiatic periods. The tracings were taken 2 days apart. In the interval the patient received
15 nig dextro-amiiphctamine sulfate daily in divided doses.
sents the mean concentrations of sodium,
potassium, and phosphorus during the
ex-peniments, as compared to those of similarly studied normal stibjects. The concentration of pt1ssitmm in plasma increased during the
experiments by an average of 20% above
the values obtained in the pre-attack period,
although the maximum concentration
meas-tired was not always above the normal
range. Experiment 4 represents an exception
to this statement. In Experiment 3, the
averaged pre-attack figure is misleading
since it includes the maximal concentration
of potassium in the plasma, which was
ob-taille(! 15 minutes before paresis became
evident (Fig. 4).
Although the averaged concentrations of
soditim in the plasma do not indicate a
sig-nificant change during the attack period,
the concentration was elevated during
pare-sis on four occasions with values as high as
155 meq/l recorded. On two occasions
con-centrations in both arterial and venotis blood
were elevated, and on another occasion only
the venous concentrations were elevated
above pre-attack levels. In the fourth
in-stance (Experiment 1) a single sample of
venous blood was obtained during an attack
and neither capillary nor arterial samples
were taken.
The concentration of phosphorus in
ye-nous plasma changed little or not at all
during paralytic attacks. In recovery, the
depression of concentration of phosphorus
in plasma was similar to that observed in
control subjects. Concentration of calcium,
carbon dioxide content, and pH in plasma
of venous blood were not altered
signifi-cantly during the experiments and all values
were within the normal range. No significant
change in concentration of magnesium in
pa-TABLE III
tient RKr. In patient JSp, Sr., who developed
subjective symptoms of an attack, the
con-centration of magnesium in the plasma grad-ually decreased from 1.7 meq/l to 1.3 meq/l,
at which time the concentration of
potas-sium in the plasma was maximal. The
con-centration of magnesium in the plasma
re-turned to a value of 1.6 meq/l while the
con-centration of potassium remained elevated.
Concentrations of sugar in the blood did
not change appreciably during any of the
experiments unless influenced by the
ad-ministration of epinephrine, glucagon, or
glucose. It will be noted that patient JSp.,
Jr., developed an attack within 25 minutes of
ingestion of glucose. The curve of
concen-trations of sugar in the blood indicated a
normal rise and satisfactory intestinal
ab-sorption btit the expected fall in
concentra-tion of potassium in the plasma did not
occur.
There was some variation in
concentra-tion of protein in the plasma but in none of
the experiments was there a rise in
con-centration sufficient to account for the
ele-vation of concentrations of potassium in
plasma.
The rate of urinary excretion of potassium
was increased coincident with the rise in
concentration of potassium in the plasma
and continued at this or a higher
concentra-tion in spontaneous recovery (Table III).
This
increase was not always sufficient toaccount for the fall in concentration of
po-tassium in the recovery period. In
Experi-ment 4 there was a precipitous fall in
con-centration of potassium in the plasma and
relief of paresis after administration of
epinephrine, even though the rate of
un-nary excretion of potassium diminished at
the same time.
The rate of excretion of sodium increased
during spontaneous recovery from attacks
in two patients but showed little consistency
in pattern in most experiments. Urinary
ex-cretion of phosphorus increased during and
after attacks.
A significant
increase
in
the
rate
of
ex-cretion of water was noted in two of the five
patients and this diuresis was not observed
in the control patients treated in similar
fashion.
DISCUSSION
There can be little doubt that the three
families which we have studied suffer from
an hereditary disease identical to the cases
described by Gamstorp et al.8 and
charac-tenized by paretic episodes associated with
elevation of concentration of potassium in
STUDIES OF URINARY ExcIIETI0N IN PATIENTS WITH HYPERKALEMIC PERIODIC
PARALYSIS AND IN CONTROL SUBJECTS
Rates of Urinary Excretion
Period Flow K Na P Creatinine
(mi/mm)
(meq/min) (meq/min) (mg/mm) (mg/mm)5 Patients Pre-attack 0.85 0.05 0.09 0 .24 0.64
5 Patients Pre-attack and attack 1.86 0.09 0.11 0.35 0.67
6 Patients (2 umltreated) Post-attack 1 .33 0 .09 0 .09 0.48 0.73
(2.14) (0.13) (0.18) (0.58) (0.63)
5 Normal subjects Control 0.90 0.06 0 .08 0 .34 0.69
.5Normal subjects After glucagon or
epi-nephrine 0.72 0.08 0.10 0.43 0.79
The figures represent mean values of determinations made during each period. Because the time of omiset of an attack was not predictable, the specimens collected during an attack contained considerable amounts of pry-attack
urine. Average urinary excretions of creatinine show only small changes which are insufficient to explain the
ARTICLES
the serum. In the absence of decreased rate
of urinary excretion of potassium, the cause
of the increase in concentration of
potas-sium in plasma must be a shift of potassium
from the intracellular to the extracellular
space since our studies of total
concentra-tion of protein in plasma do not indicate a
shift of water in the opposite direction of
sufficient magnitude to account for the
change in concentration of potassium. In
recovery, a shift of potassium from the
ex-tracellular to the intracellular space must
occur since an increased urinary excretion
of potassium could not always account for
the fall in concentrations in the plasma.
The observed rise in concentration of
sodium in the plasma has not been a
con-stant finding but has been striking when
detected. On these occasions, the
concen-tration of sodium appears to rise some time
after the rise in concentration of potassium
has occurred. In Experiment 6, the high
concentration of sodium in venous plasma,
with little change in the concentration in
capillary plasma, suggests that sodium is
being released by the tissues of the forearm.
The significance of this variable change will
require further study.
The increase in rate of excretion of water
noted during experiments with the two
members of the Kr family is of interest.
These patients had reported the occurrence
of polyunia for a short time after attacks at
home. In two of the four studies in which
this observation was made, urinary
osmolar-ity was determined and the results indicated true water diuresis.
The elevation and peaking of the T waves
Ill the electrocardiogram before and during
attacks are similar to the changes seen with
more marked elevation of concentration of
potassium in plasma in other disease states.
After administration of glucagon and
epi-nephnine, there was marked flattening of the
T wave
and
the
rise
of a U wave
coincident
with a rapid fall in concentration of
potas-sium in plasma. It is of interest to note that
after administration of glucagon to patient
RKr
these
changes
occtirred
at a time
when
the concentration of potassium in venous
plasma was 5.0 meq/l. Such T wave changes
have been described as characteristic of
hypopotassemia and as occurring during an
attack of paralysis in a patient with
hypo-kalemic periodic paralysis.’9
In both
the
patient
with
hypokalemic
pe-riodic paralysis and in the patients studied
here, the electrocardiographic changes
char-acteristic of hypopotassemia occur at a time
when potassium can be deduced to be
shift-ing from the extracellular to the intracellu-lar space.2#{176} Yet, in the first instance, this
shift accompanies paralysis of skeletal
mus-cle, and in the latter instance, paralysis of
skeletal muscle is relieved. It is clear that
the electrocardiographic changes at this
par-ticular moment are dissociated from the
fac-ton or factors resulting in paralysis of
skele-tal muscle in these diseases.
The finding of abnormal
electroencephal-ograms in two asymptomatic patients is in
contrast to the two studies performed by
Gamstorp
et a!.8
before and during an attackof paralysis, which were interpreted as
nor-mal. In the study by Ecker and Carson9 the
patients with familial periodic paralysis not
helped by administration of potassium had
abnormal electroencephalograms, while the
unaffected father of the family had a
nor-mal record.
Treatment
As reported
by Gamstorp
et al.8 andcon-firmed in the clinical history of the Kr
fam-ily, frequent small carbohydrate feedings
between meals would appear to have some
effect in decreasing the frequency and
se-verity of attacks. Our choice of glucagon,
epinephrine, and glucose for trial in therapy
was determined by their effect of reducing
concentration of potassium in the plasma
coincident with the resulting increase in
concentration of sugar in the blood.2
How-ever, in Experiment 7, administration of
glucose with adequate absorption had no
noticeable effect on the paralytic attack, and
in Experiments 8 and 9, the intramuscular
injection of dextro-amphetamine resulted in
a fall in concentration of potassium in the
change in concentration of sugar in the
blood. One of the patients studied by
Schoenthalbo in 1934 was treated with 0.025
gm of ephednine hydrochloride
adminis-tered twice daily and the patient stated that
the attacks became less severe.
In an effort to spare the patient the
dis-agreeable task of parenteral administration
of epinephrine hydrochloride at home, we
have made use of dextro-amphetamine
sul-fate.#{176}Two patients from the Kr family and
one from the Sp family have been treated
with 10 to 15 mg of dextro-amphetamine sulfate in the Spanstile form daily for from
3 to 7 months. Patient RKr has been free
of attacks except when he inadvertently
omitted medication on two occasions and
during a 2-week period when placebos
were substituted for the medication.
Pa-tient NIKr was 7 months pregnant and
hay-ing frequent severe attacks at the time
ther-apy was started. She was free of attacks
during the remainder of pregnancy and
during the puerperium when from past
ex-perience she might have expected to have
had severe episodes of paresis. The third
patient has shown definite improvement in
that attacks are less severe and only occur
after much longer exposure to cold than
formerly was necessary to produce an
at-tack.
Administration of dextro-amphetamine
sulfate to patient JSp, Jr., for 2 days before
a repeated electroencephalogram, led to
re-markable improvement in the record (Fig.
6).
The mode of action of dextro-ampheta-mine sulfate in causing a fall in
concentra-tion of potassitim in the plasma requires
further investigation.
SUMMARY
The clinical histories of three families are
described, who have a variant of familial
periodic paralysis characterized by high
concentration of potassium during paralytic
0 Supplied as Dexcdrine Spansules#{174} through the courtesy of Smith, Kline and French Labora-tories.
episodes unassociated with diminished
un-nary excretion of potassium. Data are
pre-sented concerning five hospitalized patients
from the three families. The data indicate
that the rise in concentration of potassium
in serum results from a shift of potassium
into the extracellular phase. During the
re-covery period potassium travels in the
op-posite direction.
The administration of glucagon or
epi-nephnine during an acute attack terminated
the attack promptly. The administration of
10 to 15 mg of dextro-amphetamine sulfate
daily in Spansule#{174} form effectively
con-trolled symptoms in two patients, and
re-stilted in definite improvement in a third
patient, treated for periods varying from 3
to 7 months.
REFERENCES
1. Schachnovitsch: Em Seltener Fall von
Intermittierender Paraplegic. Russk.
Vrach., 3:537, 1882.
2. Biemond, A., and Daniels, A. P. : Familial
periodic paralysis and its transition into
spinal muscular atrophy. Brain, 57:91, 1934.
3. Walker, M. B. : Potassium chloride in
myasthenia gravis. Lancet, 2:47, 1935.
4. Aitken, R. S., Ahlott, E. N., Castleden,
L. I. M., and Walker, M. B. : Observa-tions on a case of familial periodic
pa-ralvsis. Clin. Sc., 3:47, 1937.
5. Allott, E. N., and McArdle, B. : Further oh-servations on familial periodic paralysis.
Clin. Sc., 3:229, 1938.
6. Talbot,
J.
H.
: Periodic paralysis. Medicine,20:85, 1941.
7. Gammon, G. D., Austin,
J.
H.,
Blithe,
M. D., and Reid, C. G. : The relation of
potassium to periodic familial paralysis.
Am.
J.
M. Sc., 197:326, 1939. 8. Gamstorp, I., Hauge, M., Helweg-Larsen,H.
F.,
Mj#{246}nes,H.,
and
Sagild,
U.:
Adynamia episodica hereditaria: a
dis-ease clinically resembling familial
pen-odic paralysis but characterized by
in-creasing serum potassium during the
paralytic attacks. Am.
J.
Med., 23:385, 1957.9. Ecker, I., and Carson, M.
J.
: Familialperiodic paralysis.
J.
Pediat., 42:751,1953.
ARTICLES
77311. Tyler, F. H., Stephens, F. E., Gunn, F. D.,
and Perkoff, G. T. : Studies in disorders of muscle. VII. Clinical manifestations and inheritance of type of periodic pa-ralvsis without hypopotassemia.
J.
Clin. Invest., 30: 492, 1951.12. Wooster, H. A., Jr. : Nutritional Data, 2nd Ed. Pittsburgh, H.
J.
Heinz Co., 1954. 13. Danowski, T. S., Fergus, E. B., and Egan,T.J. : Unpublished data.
14. VaIl Slyke, D. D., and Neill,
J.
M. : The determination of gases in the blood and other solutions by vacuum extraction andmanometric measurement.
J.
Biol.Chem., 61:523, 1924.
15. Somogyi, M. : Notes on sugar determina-tion.
J.
Biol. Chem., 195:19, 1952.16. Clark, E. P., and Collip,
J.
P.
: Modifiedmethod of Tisdall.
J.
Biol. Chem., 63:461, 1925.
17. Fiske, C. H., and SubbaRow, Y. : The col-onimetnic determination of phosphorus.
J.
Biol. Chem., 66:375, 1925.18. Reinhold,
J.
: Standard Methods of Clinical Chemistry, Vol. 1. New York, AcademicPress, 1953, p. 88.
19. Van Buchem, F. S. P. : The
electrocardio-gram and potassium metabolism. Am.
J.
Med., 23:376, 1957.
20. Danowski, T. S., Elkinton,
J.
R., Burrows, B. A., and Winkler, A. W. : Exchanges ofsodium and potassium in familial
pen-odic paralysis.
J.
Clin. Invest., 27:65, 1948.21. Grob, D., Liljestrand, A., and Johns, R.
J.:
Potassium movement in normal subjects;
effect on muscle functio’i Am.
J.
Med.,23:340, 1957.
CELLULAR AND HUMORAL ASPECTS OF THE
HYPERSENSITIVE STATES, edited by H.
Sherwood Lawrence,
M.D.
New
York,
Paul
B. Hoeber,
Inc.,
1959,
667 pp., $18.00.This volume collects the contributions made by the participants in a conference held at the
New York Academy of Medicine with the aid
of a grant from the National Science Founda-tion. Tile general reader will find the contents of this book an enjoyable means of becoming
acquainted with the nature and scope of
im-mtinology as it has developed in recent times.
The contents comprise a wide variety of topics
incltiding: the cellular origins, biosyntheses and metabolism of antibody; the acquisition of tol-erance to and rejection of foreign tissues;
al-lergic encephalomyelitis; the Shwartzman
re-action; agammaglobulinemia; and serum
sick-ness and related states. One may gain the im-pression that when the basic studies reviewed in this volume finally penetrate to the elucida-tion of clinical disorders, the field of allergy will cease to be so frustrating and confusing to the clinician. Experienced investigators in the field of hypersensitivity will recognize the corn-petency of the participants in this symposium and will find the comprehensive survey of the
related experimental approaches helpful in
gaining perspective as to the place of particular investigations. Medical scientists whose inter-ests are primarily in fields other than
hyper-sensitivity, but who have an intellectual
curios-ity about the present status of our knowledge of the hypersensitive states, will find this book
