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Effect of digitals on clinical symptoms and conduction variables in patients with multiple sclerosis.

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Effect of Digitah
on Clinical Symptoms
and Conduction Variables
in Patients with
Multiple Sclerosis
Ryuji Kali, MD, PhD,* Leo Happel, PhD,?
and Austin J. Sumner, MDt
Digitalis has been shown to reverse conduction block in
demyelinated nerve fibers in experimental animals. I n
the search for a symptomatic treatment of multiple sclerosis, digoxin (0.02 m g per kilogram of body weight)
was given intravenously to 7 patients with probable or
clinically definite multiple sclerosis. All of these patients
had temperature-dependent symptoms. I n 3 patients,
improvement of clinical deficits was observed concurrent with significant changes in evoked potential
findings. Digitalis derivatives may be useful in ameliorating symptoms in selected patients with multiple
sclerosis.
Kaji R, Happel L, Sumner A. Effect of digitalis on
clinical symptoms and conduction variables
in patients with multiple sclerosis.
Ann Neurol 1990;28:582-584
Multiple sclerosis is a central nervous system (CNS)
disease characterized by central tract demyelination.
From the *Department of Neurology, Kyoto University Hospital,
Kyoto, Japan, and the TDepartment of Neurology, Louisiana State
University Medical Center, New Orleans, LA
This paper was presented at the 114th Annual Meeting of the
American Neurological Association, New Orleans, LA, September
1989
Received Feb 6, 1990, and in revised form May 1 Accepted for
pubhcation May 2, 1790
Address correspondence to Dr Kaji, Department of Neurology,
Kyoto University Hospital, Sakyoku, Kyoto 606, Japan
Failure of nerve impulse propagation through areas of
demyelination, that is, conduction block, is the most
important physiological consequence of demyelination
[l}. In patients with temperature-dependent neurological deficits, the reversibility of symptoms related to
temperature changes has been ascribed to reversal of
conduction block. It would be an important therapeutic advance if pharmacological agents could be identified that reverse conduction block in demyelinated ax-
ons.
To date, limited success has been reported with
the use of the potassium channel-blocking agent, 4aminopyridine [2], but this agent produces potentially
serious side effects [3, 41. A n alternative approach was
implied by the observation of Bostock and Grafe [ S ]
that activity-dependent excitability changes in peripheral demyelinated axons are the result of hyperpolarization mediated by the sodium-potassium pump. Similar hyperpolarization in CNS myelinated axons was
recently observed by Gordon and colleagues {6}. Inhibition of this pump by the cardiac giycoside, digitalis,
could theoretically reverse conduction block by lowering the threshold for excitation under such conditions.
W e have shown this to be the case in previous experimental studies [7, 81. T h e present article reports
observations indicating that digitalis does have a measurable effect in improving nerve conduction and
ameliorating clinical symptoms in selected patients
with multiple sclerosis.
Patients and Methods
Four women and 3 men (age range, 27 to 56 years), who had
clinically definite or probable multiple sclerosis b y Mc Alpine's criteria {9] as well as temperature-dependent symptoms, were entered into the study after giving informed consent. Patients with cardiac or renal diseases or low serum
potassium levels (less than 3.5 mEq per liter) were excluded.
The protocol of the clinical study was approved by the Institutional Review Board of Louisiana State University Medical Center.
Before treatment, 7 patients had pattern-reversal visual
evoked potentials (VEPs); 4 patients had somatosensory
evoked potentials (SEPs) after tibial nerve stimulation; and 4
patients had brainstem auditory evoked potentials (BAEPs).
All conduction studies were recorded at least three times
in each patient in a room air-conditioned to 24" to 26°C.
Stimulus frequencies were 1 Hz (pattern reversal), 5 Hz
(somatosensory), or 10 Hz (auditory). Digoxin (0.02 mg per
kilogram of body weight) diluted in normal saline solution
was given intravenously for 1 hour by drip infusion, while
the electrocardiogram was monitored. Evoked potentials
were retested at variable intervals ranging from 3 hours to 17
days after treatment. During each recording session, measurements included visual acuity, I-V interpeak latencies
(IPLs),and VII amplitude ratios in patients with BAEPs, and
latencies and amplitudes of Pl00 in those with VEPs or P40
in those with tibial SEPs.
Because serum and cerebrospinal fluid (CSF) levels of digoxin rapidly fall in 3 days [lo], measurements made from 3
582 Copyright 0 1990 by the American Neurological Association
Changes in Physiological Variables and Clinical Symptoms
-~~
~~
Vanable
Paticnr 1
Patient 2
Patient 3
Patient 4
Pmtm 5
Patient 6
Patient 7
A S P (Yr),
WY
40, F
56, F
35, M
33. M
14, F
2i €
34, M
TEST MET HOD
BAFPs (R)
VEPs (P100, I J
Latcn~t
(mK0
Amplitude
(&V)
I-V IPL
lmsec)
NA
0.0 r 0.0
(n = 31
4.26
V/I Ampli
tude Ram
VEPs IP100, R)
Tibial SEPs !P10, R)
BABPr (L,
Amplitude Larenr) Amplrtude I-V IPL
[FV)
(mscc)
(msec) ( p V )
latency
(msec)
VEPs lP100, R)
V/I Ampli- latency
rude Ratio !msrc)
VEPS (P100, L)
Amplitude Latency
(pVi
unsec)
Amphtude
(pVi
2.9 r 0.3
!,a = 3)
~~
Befortli$oxin
With dlgoxm
(0-72 h afrer
infusion!
Ajrcr&,xin
(72 hri)
pvalue(~UskalWallis)
128 -+ 3
= 3)
5.2 t 2.0
3 99
.(
(n - 3 )
(fi
120
0 5 2 1.3
(n = 6y
0.01~
(n = 1)'
NA
Incrcascd visual
ClLniCal
symptom
aCUlty
i20/400-
20ILOo)
+
0.00
( n = j)
=
2
0.06
3)
4.26 i 0.00
(rt = 31
3
1.6 2 0.9
43 2 1 1.6 F 0.2
(n = 31 (n = 3)
4.40 f (1.06 0 5 _t 0.1
In = 3 )
!n = 3 )
146 2 8
(n = 31
3 j -+ 0.5
141 f 2
= 3)
(n = 3)
4.04 5 0.08 0.8 2 0.1
( n = 31
(n
3)
146 -c 6
(n
4.1 r 0.7
( m = 31
1.0 i 0.1
162
in = j)
In = 3 )
( n = 3)
1.0 i 0 1
= 31
142
4
3)
4 2 r 0.8
(97 - 3)
48
(n
(12
liS 2 5
= 3i
4 1 2 1.6
in = 31
O.Oib
066
48 t 1 l.R 5 0.2 4.39 k 0.08 0.5 t 0.1
!n = 3) (n = 3)
(n = 3 )
(n = 3 )
0.25
0.15
0.06
006
(n
1.2? 0.3
3)
0.44
!n
Improvement in
double vision
~
?
2
1
Increased visual
acuity (2015020/301
z 2 2.2
(m =
3)
(?A
I
0.4
=
3)
Sublecnve mprovr- No change
mrnt in gat
~
~
3)
(72
in
1482 3
= 1)
(71
0.97
0.66
3.5 -r 0.6
N o change
= 3)
134 +- 2
3.4 t 0.4
(n = 3)
(n
(n =
143 c 3
3)
(n = 3)
0.08
0.24
=
3)
3.0 z 0.i
No change
'The numbers of samples were different between mplimde mnd latency mesureinents because recordings mthout PI00 were e1irert.d in the amplitude samples as having zero amplitude
bStarirticdy signihcant difference ( p < 0.05).
VEPs
=
risud evoked potenuals, BAEPs = brainstem auditory evoked potentials, SEPs = sensory evoked potentials, L - left; R = rlght; IPL = interpeak latency
hours to 3 days after the infusion were compared with those
obtained before or more than 3 days after the infusivn
(Table). Data from these three groups were analyzed for
statistical significance by using the Kruskal-Wallis test [I 11.
Results
Three of 7 patients showed statistically significant
changes in evoked potential parameters concurrent
with improvements in clinical deficits (see Table). One
patient with clinical signs consistent with a transverse
cervical cord lesion (Patient 4 ) described subjective
improvement of gait disturbance that was not accompanied by significant changes in evoked potential findings. The other 3 patients showed neither clinical improvement nor significant evoked potential changes.
No adverse effects were noted except for mild prolongation (less than 0.20 seconds) of the PQ interval and
ST depression (less than 1 mm) in the EKG.
A representative patient whose symptoms responded to digoxin is described in the following case
report.
Patient 1
A 40-year-old woman was admitted to the hospital
because of paresthesia over the trunk and limbs below
the C7 dermatome on both sides as well as loss of
visual acuity in the left eye. She had previously noticed
blurring of central vision in the left eye one year before admission; this blurring subsequently disappeared
in 2 months. She had experienced paresthesias in the
feet 6 months before admission, later followed by ascending paresthesias to the level of the C7 dermatome
on both sides over the following 2 months. Visual
acuity in the left eye also decreased during this period.
Although the visual and sensory symptoms subsided
within 4 months, they reappeared after flulike symptoms 4 weeks before admission. These symptoms became worse after the patient took a hot bath or on very
hot summer days. Physical examination on admission
disclosed impaired visual acuity in the left eye (20/
4OO), nystagmus, and decreased deep qensibility below
the C7 level. After admission, the left visual acuity and
VEPs remained stable for 2 weeks before the digitalis
trial. During recording of VEPs 3 hours after digoxin
infusion, the patient's visual acuity improved to 201200
as the amplitude of the potential (P100) increased (Figure). The serum level of digoxin sampled at this time
was 1.2 nglml. The PlOO amplitude increased further
at 24 hours after infusion, but it had returned to the
baseline by 4 days after infusion; also, visual acuity had
decreased to 201400. Changes in VEPs and visual acuity were not found afrer an infusion of normal saline
solution 8 days later, when the serum level of digoxin
was less than 0.1 ngiml (see Figure).
Discussion
The present study was designed to examine short-term
clinical and physiological changes over a few days after
digoxin infusion in patients with multiple sclerosis
whose symptoms might have fluctuated spontaneously
over longer periods. The study provided the possibility
of using digitalis as a symptomatic treatment for such
patients. Although this is not a double-blind study, the
significant evoked potential changes strengthened interpretation of the clinical improvement as evidence of
digitalis effect.
In addition to showing complete conduction block
(complete blockage of impulse conduction), demyBrief Communication: Kaji et ak Digitalis in MS 583
V.A.
201400
12 days
201400
Digoxin 1 2 rng I v
+3 hrs
20/200
c,
20/200
+24 hrs
P i 0 0 (123 msec)
+4 days
b-k+----
+8 days
201400
201400
partly by poor penetration of digoxin through the
blood-brain barrier [lo]. Tissue concentration of digitalis may not reach an effective level in plaques where
the blood-brain barrier is not totally compromised, or
the increase in serum level of digoxin may be too transient to give the optimum level in the plaque. In addition, expected tissue concentrations of digoxin would
be much lower in this clinical study than in the previous animal studies that used at least 0.3 mgikg of
intraperitoneally administered ouabain {7]. As such,
intravenously given digoxin is not expected to be of
general clinical use. Orally given digoxin may be clinically useful for attaining more sustained serum levels
of the drug, and a clinical study using orally given
digoxin is now in progress. A digitalis derivative with
higher penetration through the blood-brain barrier
would bc an even better candidate for clinical use, if it
becomes available.
201400
+12 days
1 5 P V
50 msec
Serial recordings of visual euoked potentiah (VEP.rj before ( - )
and after ( + ) infusion of digoxin. A t 7 days afier infusion.
normal saline solution was infused, but no significant changes in
VEPs were obserued 24 hours later (
8i
days). (i.v. = intraoenously: V.A. = visual acuity.)
This study was supported by grant no. RG-2099-A-1 from the National Multiple Sclerosis Society and by Grant-in-Aid for General
Scientific Research (A) 01440096 from the Ministry of Education,
Science and Culture, Japan.
We wish to thank Dr A. K. Asbury for helpful comments. Dr
J. Kimura kindly referred a patient to this study.
References
elinated nerve fibers cannot sustain high-frequency (10
to 50 Hz o r more) impulse conduction despite normal
conduction at lower frequencies [ S , 12). This ratedependent block, or failure to transmit high-frequency
impulses, has been ascribed to membrane hyperpolarization mediated by sodium-potassium pump activation
[ 5 ) , and it may interfere with neural function in the
CNS, where the information is coded in frequencies of
impulses up to 250 Hz or more 1121.
The specific pump inhibitor, digitalis, restores ability
to maintain high-frequency impulse transmission in
central and peripheral demyelinated fibers [ 7 , 8). It has
been found that digitalis also reverses complete conduction block in peripheral demyelinated fibers, possibly by reducing the resting membrane potential 181.
The present study used relatively low stimulus frequencies (10 Hz or less) for evoked potential tests.
The observed changes in conduction variables are
probably the effect of digitalis on complete conduction
block. Therefore, the effect of digoxin on ratedependent block may escape detection by the conduction studies we used, even though it improved clinical
disabilities as in Patient 4.
The clinical and physiological changes were transient
and modest, and not all the patients responded to the
drug. These limitations are perhaps caused partly by
OUT method of single intravenous administration and
584 Annals of Neurology
Vol 28 No 4 October 1990
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conduction block in vivo. Ann Neurol 1989;25:159-165
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