Transcript Exercise Testing in Channelopathies

Exercise Testing in
Channelopathies
Indications
• Periodic Paralysis
• Myotonic Disorders
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Dystrophic
Nondystrophic
Paramyotonia
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Myasthenia gravis
Eaton-Lambert
Botulism
Congenital myasthenic syndromes
• Neuromuscular junction Disorders
Scientific Background
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Resting State
Resting membrane potential
-85mV
Na+ and Ca+ concentrations
higher extracellularly than
intracellularly
K+ and Cl- concentrations
higher intracellularly than
extracellularly
Constant balance between
high intracellular K+ and low
intracellular Na+ by active
transport through specific ion
channels
Scientific Background
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Ion Channels
Ion specific channels are macromolecular proteins spanning lipid
bilayer of cells and can be opened or closed.
Ions can flow through open channels
Flow depends on:
Electrochemical gradient
Relative permeability
Relative selectivity of the channel
Voltage depend gating: gating is mediated by channels sensitivity to
electrical potential changes of the membrane.
Other channel types: some do not require a change in voltage to
open or close e.g. ligand gated channels, exchangers, transporters
etc
Scientific Background
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Depolarization
Threshold is reached.
Voltage gated Na
channels activated,
leading to increased
Na conductance and
thus fast Na influx
into cell.
Scientific Background
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Repolarization
With change in
polarity, inactivation
of Na channel occurs,
K and Cl conductance
rises
Therefore, K out and
Cl in, reestablishing
negative resting
membrane potential.
Model for membrane
excitability disorders
• Membrane excitability
is a balance between
excitation and
inhibition.
Model for membrane
excitability disorders
Excitatory influences (ex)
Inhibitory influences (iy)
Glutamate receptors
Na channels
Ca channels
GABA receptors
K channels
Cl channels
E= (e1+e2+e3)- (i1+i2+i3)
Model for membrane
excitability disorders
• Physiological effects of SCN4A and ClCN1
mutations e.g. hyperkalemic periodic paralysis,
paramyotonia congenita, Myotonia congenita.
Diseases of Ion Channels
Ion channels found in:
• muscle: periodic paralysis, myotonia
• brain: epilepsy, familial hemiplegic
migraine, episodic ataxia
• heart: long QT syndrome, Andersen-Tawil
syndrome
Protocol for Evaluation of
Myotonia & Periodic Paralysis
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1. Routine motor & sensory nerve conduction studies in upper & lower limbs.
2. EMG: include distal, proximal, facial and paraspinal muscles.
3. Muscle cooling if suspicion of paramyotonia congenita.
a. Wrap arm in plastic bag, immerse in ice water for 10-20 min till skin temperature is
20°C. Remove hand if weakness develops.
b. EMG hand muscle.
c. Allow muscle to rewarm to precooling temp & continue to record EMG (may take
>1 hour)
4. Short exercise test if above test does not yield definitive result.
a. Immobilize hand. Record ADM CMAP (Make sure immobilize hand).
b. Record CMAP every minute for 5 minutes with muscle at rest to ensure stable
baseline.
c Perform max voluntary contraction for 10 sc.
d. Record CMAP immediately. If a decrement in CMAP is seen, continue to record
CMAP every 10 seconds till returns to baseline (usually 1-2 mins).
e. In cases where decrement is seen after exercise, repeat same procedure several
times to see if reduction in CMAP continues or habituates.
Protocol for Evaluation of
Myotonia & Periodic Paralysis
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5. Prolonged exercise test if above do not provide diagnostic clues.
a. Immobilize hand. Record ADM CMAP (Make sure immobilize hand).
b. Record CMAP every minute for 5 minutes with muscle at rest to ensure stable baseline.
c. Perform max voluntary contraction for 5 minutes: resting every 15 sec for 3 seconds.
d. Ask patient to relax completely.
e. Record CMAP immediately, then every 2 minutes for 60 minutes afterwards or until there is no
further decline (maybe >1 hour).
Decrement = (highest CMAP postexercise - smallest CMAP postexercise)/(highest CMAP
postexercise) X 100.
Any decrement >40% is abnormal.
f. NB: Immediately after exercise, CMAP maybe larger before slow decline in amplitude.
Comments:
CMAP often increases with cooling in NORMAL individuals.
1. Myotonia congenita may have an initial but transient decrement after exercise that quickly
resolves. Not worsened by cooling, and, as in normality, may increase with cooling.
2. Paramyotonia congenita have a prolonged decrement with combination of exercise and cooling
that is still often apparent on rewarming.
Calculations
Increment
(highest CMAP postexercise – CMAP before
exercise) X 100 /
(CMAP before exercise)
Any increment > 30% is abnormal for CMAP.
Any increment > 25% is abnormal for CMAP area.
Decrement
(highest CMAP postexercise – smallest CMAP
postexercise) X 100 /
(CMAP postexercise)
Any decrement > 40% is abnormal for CMAP.
Any decrement > 45% is abnormal for CMAP
area.
Specificity = 97.8%
Common Channel Diseases
Electrophysiologic Testing
Electrophysiologic Testing in
Channelopathies (Part 2)
Sensitivity / Specificity
• Mean sensitivity 63%
• Primary periodic paralysis 81%
• Chloride channelopathies 17%
• Thyrotoxic periodic paralysis 75%
• Specificity = 97.8%
Hypokalemic
Periodic
Paralysis:
Exercise Test
Exercise Test: Amplitude
increase
Exercise Test: Amplitude
decrease
Myotonic dystrophy
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AD, trinucleotide (CTG) disorder on Chr 19q affecting myotonin gene.
Usually present in late teens with distal weakness and delayed relaxation (milkmaid grip,
percussion Myotonia)
Stiffness that improves with repeated contractions.
Classical appearance of bifacial weakness, temporal weakness (triangular facies) , frontal balding,
ptosis, neck flexor weakness, distal muscle wasting and weakness.
Other clinical features include:
Cataracts (posterior capsule, multicolor pattern))
Cardiac conduction abnormalities
Pulmonary defects (pectus excavatum)
Endocrine dysfunction (diabetes, testicular atrophy, hypogonadism)
Hypersomina (sleep apnea syndrome)
Mild cognitive impairment
CK: mild to moderate elevation
Muscle biopsy: atrophy Type I fibres, increase in central nucleation, ring fibres, occasional small
angulated fibres.
10% congenital
Anticipation more profound when inherited from mother
Myotonic dystrophy
A three-generation family affected
with myotonic dystrophy. The
degree of severity increases in
each generation. The
grandmother (right) is only slightly
affected, but the mother (left) has
a characteristic narrow face and
somewhat limited facial
expression. The baby is more
severely affected and has the
facial features of children with
neonatal-onset myotonic
dystrophy, including an open,
triangular-shaped mouth. The
infant has more than 1000 copies
of the trinucleotide repeat,
whereas the mother and
grandmother each have
approximately 100 repeats.
Myotonic dystrophy
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Electrophysiology
Low CMAP maybe secondary to myopathy.
Myotonia most prominent in distal hand, forearm
extensor, tibialis anterior, facial muscle but not usually
found in proximal muscles.
MUAP analysis difficult if profound myotonia.
Muscle cooling ahs no effect.
Short exercise test produces drop in CMAP immediately
after exercise. If CMAP recorded every 10 sec up to 2
min, it recovers to baseline. If short exercise test
repeated, the decremental responses habituates.
Proximal Myotonic Myopathy
• AD, trinucleotide (CCTG) disorder on Chr
3q
• Weakness is mostly proximal and may
have muscle hypertrophy.
• Peculiar intermittent pain syndrome in
thigh, arms or back.
• Phenotype otherwise is very similar to
myotonic dystrophy.
Proximal Myotonic Myopathy
Electrophysiology
• Effects of cooling, short and long exercise
test not well documented.
Myotonia congenita
• Lack of weakness in most patients and absence of extramuscular
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abnormalities.
AD (Thomsen’s disease): Julius Thomsen (1876) had the disease
AR(Becker’s disease): first described by Becker
Both arise from ClCN1 abnormality on Chr7q
Minor wasting and weakness in Becker and may also have transient periods
of weakness.
Onset in infancy or early childhood.
Usually present with nonprogressive muscle stiffness.
Muscle hypertrophy is common (Herculean).
Stiffness worsens after rest, cold and diminishes with exercise (warm up
period).
Grip and percussion myotonia.
CK slightly elevated in AD form, moderately elevated in AR form.
Biopsy: may show lack of Type IIB fibres.
Myotonia congenita
Young child with
percussion myotonia
of tongue.
Myotonia congenita
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Electrophysiology
Widespread myotonic discharges, rare myopathic units in AR form.
Muscle cooling in AD form may produce myotonic bursts of longer
duration that maybe more easily elicited than at room temperature.
The short exercise test produces a CMAP immediately after exercise
which recovers over 1-2 min with repeated CMAP recording every 10
seconds.
This is unlike paramyotonia congenita in which a decremental
response recovers very slowly over many minutes.
RNS causes decrement  15% (up to 50%) similar to MG
Repairs with brief exercise, but CMAP remains 10-15% lower
In ensuring 30 sec, decrement reappears.
These responses to RNS and brief exercise characteristic of
congenital myotonia.
• Rapid RNS (>10Hz) decrement >25%
Myotonia Congenita
(Na channel)
• New syndrome that is K sensitive, SCN4A
mutation on Chr17q(same abnormality as
hyperkalemic periodic paralysis), see end
of presentation for new syndromes.
Myotonia Fluctuans
(K+ Aggravated Myotonia)
• SCN4A mutation, AD
• Symptoms occur after period of rest
following exercise
• Stiffness often painful especially around
chest.
• Marked variation in intensity of myotonia
• Myotonia aggravated by oral potassium or
carbonic anhydrase inhibitors.
Myotonia Permanens
• SCN4A mutation, AD
• Similar to myotonia fluctuans except persistent
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rather than episodic
Symptoms occur after period of rest following
exercise
Stiffness often painful especially around chest.
Marked variation in intensity of myotonia
Myotonia aggravated by oral potassium or
carbonic anhydrase inhibitors.
Paramyotonia Congenita
• Eulenburg, 1886.
• Stiffness usually affecting bulbofacial, neck &
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hand muscles.
Stiffness is brought on by repeated contraction
or exercise.
Stiffness is triggered by exposure to cold.
Infant noted to have prolonged eye closure after
crying or face washed with cool water.
Paramyotonia Congenita
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Electrophysiology
Myotonia maybe more prominent in distal muscles.
Muscle cooling may have profound effect which is pathognomic:
transient dense fibrillations appear with cooling which eventually
disappear below 28°C; as further cooling occurs, all myotonic
discharges completely disappear below 20°C giving way to paralysis
of muscle. This may last up to an hour after muscle is warmed to
room temperature.
Short exercise test may produce drop in CMAP which may show
marked delay in recovery to baseline CMAP up to an hour (unlike
myotonic dystrophy and Myotonia congenita); muscle cooling maybe
necessary in some patients to bring out the decremental response.
RNS no decrement unless muscles cooled or after exercise.
Hyperkalemic periodic
paralysis
• Attacks of periodic weakness provoked by
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fasting, rest after exercise or cold.
Attacks are brief, lasting minutes to hours, and
accompanied by hyporeflexia.
K is usually elevated during attacks.
Attack relieved by ingesting carbohydrates.
Develop progressive weakness during adulthood.
Hyperkalemic periodic
paralysis
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Electrophysiology
May not have myotonia between attacks.
Rarely myopathic units.
Myotonia seen early in the attack but disappear as weakness
progresses.
Muscle cooling ahs no effect.
Short exercise test produces no decrement.
Long exercise test produces immediate increase in CMAP, especially
if initial CMAP is low. Followed by progressive decline in CMAP by
50% over 20-40nminutes with most of decline in the first 20
minutes.
RNS causes no decrement unless after prolonged exercise.
Hypokalemic Periodic Paralysis
• Usually present in teenage yeas
• Attacks can be prolonged, usually occurring on
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awakening and accompanied by hyporeflexia
K is low during attacks
Myotonia is never present.
Eventually, proximal myopathy.
Rarely associated mild sensory axonal
polyneuropathy.
Hypokalemic Periodic Paralysis
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Electrophysiology
Rarely associated mild sensory axonal polyneuropathy.
Never myotonia
Effects of cooling unknown.
Short exercise test causes no decrement.
Long exercise test produces immediate increase in CMAP,
especially if initial CMAP is low. Followed by progressive
decline in CMAP by 50% over 20-40nminutes with most
of decline in the first 20 minutes.
RNS causes no decrement unless after prolonged
exercise.
Other Muscle disorders
associated with Myotonia
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Acid maltase deficiency
inflammatory: polymyositis
congenital: myotubular myopathy
drugs (clofibrate, statins, propranolol,
fenoterol, terbutaline, colchicine,
penicillamine, cyclopsorin)
Exceptions to the Rule
Channelopathies always thought of as
disorders of fast inactivation, but newly
discovered diseases due to slow
inactivation.
Hayward LJ, Sandoval GM, Cannon SC. Defective slow inactivation of sodium channels contributes to
familial periodic paralysis Neurology, Apr 1999; 52: 1447.
Slow Inactivation of Na Channel
(Heat Sensitive)
Sodium currents by perforated
patch clamp from wild-type (WT)
and P1158S Na+ channels in
transfected tsA201 cells at 22 and
32 °C. Test 10-millisecond pulses
were given every 5 seconds to a
potential between -80 and 35 mV
from the holding potential of -100
mV. WT Na+ currents at 22 °C
(a) and 32 °C (b) are shown.
P1158S Na+ currents showed a
slower inactivation time course
and slight late currents at both
22 °C (c) and 32 °C (c). I to V
curves of Na+ current recorded
by perforated patch clamp at 22
°C (e) and 32 °C (f) are also
shown. Test 10-millisecond pulses
were given every 5 seconds to a
potential between -80 and 35 mV.
Filled squares = WT, 22 °C; filled
triangles = P1158S, 22 °C; open
squares = WT, 32 °C; open
triangles = P1158S, 32 °C.
Exceptions to the Rule
Hypokalemic paralysis always thought of as Ca channel
disease, new families discovered with mutation in
SCN4A.
Japanese family with AD heat induced myotonia and cold
induced paralysis with hypokalemia.
Bulman DE. Scoggan KA. van Oene MD. Nicolle MW. Hahn AF. Tollar LL. Ebers GC. A
novel sodium channel mutation in a family with hypokalemic periodic
paralysis. Neurology. 53(9):1932-6, 1999 Dec 10.
Sugiura Y. Aoki T. Sugiyama Y. Hida C. Ogata M. Yamamoto T. Temperaturesensitive sodium channelopathy with heat-induced myotonia and coldinduced paralysis. Neurology. 54(11):2179-81, 2000 Jun 13
SCN4A Mutations
Multiple Phenotypes
KPP: Kalemic Periodic Paralysis
PC: Paramyotonia Congenita
PAM: Potassium Aggravated Myotonia
Exceptions to the Rule
Multiorgan involvement : paramyotonia congenita with SCN4A mutation affecting
cardiac repolarisation.
Andersen-Tawil syndrome: mutation in K channel causes dysmorphic features, long
QT, periodic paralysis. Exercise test is similar to periodic paralysis. New channel
mutations.
Pereon Y. Lande G. Demolombe S. Nguyen The Tich S. Sternberg D. Le Marec H. David A.
Paramyotonia congenita with an SCN4A mutation affecting cardiac repolarization.
Neurology. 60(2):340-2, 2003 Jan 28.
M. R. Donaldson, J. L. Jensen, M. Tristani–Firouzi, R. Tawil, S. Bendahhou, W. A. Suarez, A. M.
Cobo, J. J. Poza, E. Behr, J. Wagstaff, P. Szepetowski, S. Pereira, T. Mozaffar, D. M. Escolar, Y.-H.
Fu, and L. J. Ptácek PIP2 binding residues of Kir2.1 are common targets of mutations
causing Andersen syndrome Neurology 2003 60: 1811-1816
Katz JS. Wolfe GI. Iannaccone S. Bryan WW. Barohn RJ. The exercise test in Andersen
syndrome. Archives of Neurology. 56(3):352-6, 1999 Mar
S. Sampaolo, A. A. Puca, V. Nigro, V. Cappa, V. Sannino, G. Sanges, V. Bonavita, and G. Di Iorio
Lack of sodium channel mutation in an Italian family with paramyotonia congenita
Neurology 1999 53: 1549
Andersen-Tawil
Syndrome
Syndactyly of the second and
third toes on the left foot is
evident, and toes on the right
foot are dramatically
shortened. The patient
possesses a small, reduced
chin and broad, flat nose—
typical physical features
associated with Andersen-Tawil
syndrome. In the
accompanying EKG, asterisks
denote sinus beats, and
overhead bar designates
bidirectional ventricular
tachycardia.
Exceptions to the Rule
Compound heterozygotes confounding the
diagnosis!!!
S. Nagamitsu, T. Matsuura, M. Khajavi, R. Armstrong, C. Gooch, Y. Harati, and T. Ashizawa A
"dystrophic" variant of autosomal recessive myotonia congenita caused by novel
mutations in the CLCN1 gene Neurology 2000 55: 1697-1703.
S. Nagamitsu, T. Matsuura, M. Khajavi, R.
Armstrong, C. Gooch, Y. Harati, and T. Ashizawa
A "dystrophic" variant of autosomal
recessive myotonia congenita caused by
novel mutations in the CLCN1 gene
Neurology 2000 55: 1697-1703.
The proband shows
muscular hypertrophy
of the quadriceps and
hamstring and
atrophy of the distal
forearm and distal
lower leg muscles. He
has no "hatchet"
facies or frontal
baldness.