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Hypokalemic

Periodic Paralysis

Definition

Hypokalemia is defined as a potassium level


less than 3,5 mEq/L.
Moderate hypokalemia is a serum level of
2.5-3 mEq/L.
Severe hypokalemia is defined as a level
less than 2.5 mEq/L.

The reference range for serum potassium


level is 3.5-5 mEq/L

PATHOPHYSIOLOGY
Total body deficit
of potassium

chronic inadequate intake,


long-term diuretic or laxative use,
chronic diarrhea, hypomagnesemia &
hyperhidrosis

Acute potassium
depletion

diabetic ketoacidosis,
severe GI losses : vomiting / diarrhea,
dialysis, and diuretic therapy

potassium shifts
from the EC
to IC space

Alkalosis & hypothermia


insulin,
catecholamines

Other causes

Distal RTA & Bartter syndrome,


Periodic hypokalemic paralysis,
Hyperaldosteronism & hyperthyroid.

Abnormalities of serum potassium are associated with well described


clinical features:

S. K+ level

Clinical features

<3.5 mmol/l

Lassitude

<2.5mmol/l

Possible muscle necrosis

<2 mmol/l

Flaccid paralysis with


respiratory compromise

Definition

Serum potassium of less than 3.5 mmol/L.

Effects of hypokalemia
Atrial/ventricular

Arrhythmias are more


common in patients with underlying
heart disease (especially CAD) and in
patients taking digoxin.

life-threatening

Cardiac Arrhythmias can


occur when the serum potassium is very
low (< 2 meq/L), or when the serum
potassium is relatively low (2 - 3 meq/L)
in patients with underlying heart disease,
or when the patient is digoxin-toxic.

Effects of hypokalemia
severe

(or rapidly occurring)


hypokalemia can cause muscle
weakness and paralysis the paralysis
mainly affects the proximal lower
extremities => progressing to affect
the upper extremities; dysphagia and
dysarthria are uncommon and cranial
nerve palsies are exceedingly rare)
Rhabdomyolysis can occur in severely
potassium-depleted patients especially following vigorous exercise
- and muscle necrosis can rarely
occur

Effects of hypokalemia
hypokalemia

produces a carbohydrateintolerance (? due to impaired insulin release


and ? impaired insulin resistance) =>
worsening hyperglycemia in diabetics.

hypokalemia

also produces a metabolic


alkalosis (by ? stimulation of bicarb absorption
by the proximal tubule and ? renal
ammoniagenesis)

hypokalemia

can contribute to the


development, or worsen the symptoms, of
hepatic encephalopthy (? due to renal
ammoniagenesis)

Investigations
Although

ECG changes may be helpful if


present, their absence should not be taken as
reassurance of normal cardiac conduction.
The ECG in hypokalemia may appear normal
or may have only subtle findings immediately
prior to clinically significant dysrhythmias.
During therapy, monitor for changes
associated with over-correction and
hyperkalemia including prolonged QRS,
peaked T waves, bradyarrhythmia, sinus node
dysfunction, and asystole.

The ECG findings in hypokalemia:


Ventricular dysrhythmia, Prolongation of QT interval, ST
segment depression, T wave flattening& U waves.

Investigations
Drug

screen (serum or
urine):
Amphetamines

and other
sympathomimetic
stimulants can cause
hypokalemia.

Other

drugs include

verapamil

overdose.

Theophylline.
amphotericin

B.

Aminoglycosides.
cisplatin.

Hormonal assay:
Serum ACTH,
Cortisol,
Renin activity,
Aldosterone

Hypokalemic
Periodic Paralysis
(HypoPP)

Hypokalemic Periodic Paralysis (HypoPP)


prevalence:

1:100,000; dominant transmission

onset of disease:

childhood or puberty

clinical features:

weakness episodes (at younger age) and/or


permanent weakness, a progressive myopathy

weakness episodes:

up to daily for several hours

Provocative factors:

carbohydrates, sodium, resting periods after


exercise, mental stress, cooling, fever, cortisol
induce a drop in serum potassium

between episodes:

blood potassium is normal

etiology:

voltage sensor mutations (Na+, Ca2+ channels)

Na+ and Ca2+ CHANNELOPATHIES


Na+ channel (NaV1.4)

Potassium aggravated myotonia


Paramyotonia congenita
Hyperkalemia periodic paralysis
Hypokalemic periodic paralysis

Ca2+ channel (CaV1.1)


Hypokalemic periodic paralysis

CHANNELOPATHIES IN SKELETAL MUSCLE

Na+ CHANNELOPATHIES

Na+ CHANNELOPATHIES

From Hayward et al. 1999. Neurology 52:1447

Familial periodic paralysis

rare autosomal dominant disorder


characterized by transient episodes of
profound hypokalemia thought to be due
to sudden abnormal shifts of K into cells.

Episodes frequently involve varying


degrees of paralysis.

They are typically precipitated by a large


carbohydrate meal or strenuous exercise.

clinical features

most patients are asymptomatic

moderate-severe hypokalemia : muscle weakness and restless


legs, cramps.

profound hypokalemia : muscle paralysis (serum potassium <


2 mmol/L)

cardiac arrhythmias in elderly patients with underlying heart


disease

Hypokalemia potentiates the effects of digoxin and may cause digitalis intoxication

ECG changes :

The typical finding of


hypokalemia include:
1) depression of the T
wave.
2) elevation of the U
wave.

Management

The underlying cause should be identified and


treated.

If the problem is mainly one of redistribution of K


into cells, reversal of the cause (e.g. correction
of alkalosis) may be sufficient

If hypokalemia is mild : oral K supplements are


given.

If the patient is severely hypokalemic: the


cautious infusion of intravenous K should be
considered (but not more than 20 mmol per
hour).

Periodic Paralysis

Results from persistent membrane depolarization inactivation of normal Na+


channels membrane inexcitability

HyperKPP Na+ channelopathy depolarization due to abnormal persistent INa

HypoKPP

Type I - Indirect Ca2+ Channelopathy

Type 2 - Na+ channelopathy loss of function

Hyperkalemic Periodic Paralysis


(HyperPP) - AD
episodic

attacks of flaccid weakness


myotonia is often present (vs HypoK-PP)
paralysis caused by membrane
depolarization Na+ channel inactivation
Overlap: Na+ Ch myotonias, paramyotonia

Lehmann-Horn, Rudel, Ricker

Impaired fast inactivation can


produce myotonia

1 msec

Note: Loss of inactivation in a small % of


channels myotonia
Myotonia stopped in part due to
accumulated slow inactivation

Key to Paralysis vs Myotonia is


Persistent Depolarization

Impairment of Slow Inactivation


will facilitate persistent opening
of mutant channels

Hypokalemic Periodic Paralysis


(HypoKPP) - AD
Episodic

attacks of flaccid paralysis


Myotonia never present (vs HyperKPP)
Insulin paralytic attack without K+
Membrane excitability impaired low
conduction velocity: Drs. Haenen,
Links, Oosterhuis, Stegeman, van der
Hoevan, van Weerden & Zwarts

Muscle channelopathies
Non

dystrophic myotonias

Myotonia

congenita (CLCN1)

Paramyotonia

congenita (SCN4A)

Sodium

channel myotonias (potassium


aggravated myotonias) (SCN4A)

Periodic

paralyses

Hypokalemic
Hyperkalemic
Anderson

(CACNA1S/ SCN4A)

(SCN4A)

Tawil syndrome (KCNJ2)


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Periodic Paralysis Secondary


Hypokalemic:
Thyrotoxic

periodic paralysis
hyperaldosteronism
RTA
villous adenoma
cocaine binge
diuretics, licorice, steroids, ETOH
Hyperkalemic

(k>7):

hyporenemic

hypoaldosteronism (DM/CRF)
oral K, CRF, chronic heparin, rhabdomyolysis
Normakalemic:
Guanidine,

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sleep paralysis, MG, TIA,

Hypokalemic periodic paralysis


HypoKPP1
HypoKPP
1

and 2 - CACNA1S/ SCN4A gene

1 is the most frequent form

in 100,000

Autosomal
M:F

dominant inheritance pattern

3 or 4:1

Onset:

first 2 decades of life

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Clinical features
Flaccid

paralysis mild focal weakness


to severe generalized weakness

Occur

anytime of the day; more


common in morning

Absence

of myotonia

Proximal

> distal weakness; legs > arms

Sparing

of facial, ventilatory and


sphincter muscles

Lasts

several hours to more than a day


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Frequency:

highly variable

Frequency

decreases after age 30; may


become attack free in 40s and 50s

Permanent

fixed weakness or slowly


progressive weakness more common with
HypoKPP1

Attacks

may be preceded by sensation of


heaviness and or aching in the low back
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Precipitating factors
Strenuous

physical activity followed by


rest or sleep

High

carb diet

ETOH

consumption

Emotional

stress

Concurrent
Lack

viral illness

of sleep

Medications

like beta agonists,


corticosteroids, and insulin
33

Hypokalemic Periodic Paralysis


Genetics
Mutations

in voltage sensor segment


D2S4 of 1 subunit of skeletal muscle Ca
channel gene, chromosome 1q

Arg528His,

Arg1239His, Arg1239Gly

Less

commonly SCN4A mutation


enhances Na inactivation

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Hypokalemic Periodic Paralysis


Pathophysiology
The

mutation slows the activation rate of Ltype Ca current to 30% of NL

Reduced

RYR1-mediated Ca release from

SER
Reduced

calcium current density

Impaired

E-C coupling

role of K and ? inexcitability

Ca

homeostasis change reduces ATPdependent K channel current and leads to


abnormal depolarization (Tricarico D et al
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Diagnostic studies
Serum

K < 3.0mEq/L

Serum

CK level elevated

EKG

changes U waves, flattening of T


waves

Provocative

testing - Intravenous glucose

load/ insulin
Electrophysiology
Sensory

and motor NCS normal between

attacks
During

attacks small CMAP. Reduced


insertional activity, fibs and positive sharp
waves
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Periodic Paralysis
Muscle Pathology
Muscle

biopsy reserved to atypical


patients with normal provocative and
gene testing

Vacuoles

reflect permanent myopathy

Vacuoles

represent proliferation,
degeneration and autophagic destruction
of T-tubules & SR

Large

central vacuoles in hypokalemic PP


37

Hypokalemic Periodic Paralysis

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Treatment
Reducing
Acute

exposure to known triggers

treatment replacement of K

Acetazolamide

prevent attack
recurrence and severity
Acetazolamide

may ppt weakness in

HypoKPP2
Dichlorphenamide

no longer

available
Triamterene

and spironolactone
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Diagnosing Muscle Channelopathies

R/O secondary forms

Measure K+ during attack

Provocative testing for PP: seldom done!


o

Hypo: gluc/insulin

Hyper: K+

Muscle Bx vacuoles/dilated T-tubules

Electrophysiology

EMG

Short/long exercise tests

Genetics

40

Electrophysiology: Short Exercise Test


More

useful in MC

Baseline

CMAP

Exercise

10 sec

Record

CMAP immediately post


exercise, then q 10 sec for 1
min.

CMAP in MC and PMC

PMC

exacerbated by cold

Musc. Nerve. 1982; 5: 719-723)


(Streib.
No change
in CMAP in

HypoKPP

(Fournier. Ann. Neurol. 2004; 56: 650-661) (Fournier


Neurology 2009)

41

Long Exercise Test for


Periodic Paralysis

Record

ulnar CMAP Amp baseline


Exercise ADM 5 min
Check CMAP every 2 min. for 50
min
In PP (all types), Amp immed
post ex, over next 10-40 min,
grad dec amp
In MC Amp immed post ex,
rapid return to baseline
In PMC sustained Amp
(McManis. Musc. Nerve. 1986; 9: 704-710)
(Fournier. Ann. Neurol. 2004; 56: 650-661)

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References

Dr.Barohns presentation on Muscle Channelopathies

Anthony A.Amato and James A.Russell; Non dystrophic myotonias and periodic
paralysis. Neuromuscular disorders 2008, Mc Graw Hill, Section II Chapter 29; 655680

Burge JA, Hanna MG. Novel insights into the pathomechanisms of skeletal muscle
channelopathies; Curr Neurol Neurosci Rep. 2012 Feb Vol 12:62-69

Hanna, Dipa L Raja Rayan and Michael G. Skeletal Muscle Channelopathies:Non


Dystrophic Myotonias and Periodic Paralysis. Current Opinion in Neurology, 2010 Vol.
23: 466-476

neuromuscular.wustl.edu

Doreen Fialho and Michael G.Hanna. Periodic paralysis, Handbook of Clinical


Neurology, 2007 Vol. 86 (3rd series), p 89-90

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Disease characteristics

Hypokalemic periodic paralysis (HOKPP) is a condition in which affected individuals


may experience paralytic episodes with concomitant hypokalemia (<2.5 mmol/L),
and occasionally may develop late-onset proximal myopathy. The paralytic attacks
are characterized by reversible flaccid paralysis usually leading to paraparesis or
tetraparesis but typically sparing the respiratory muscles and heart. Acute paralytic
crises usually last at least several hours and sometimes days. Some individuals have
only one episode in a lifetime; more commonly, crises occur repeatedly: daily,
weekly, monthly, or less often. The major triggering factors are carbohydrate-rich
meals and rest after exercise; rarely, cold-induced hypokalemic paralysis has been
reported. The interval between crises may vary and may be prolonged by preventive
treatment with potassium salts or acetazolamide. The age of onset of the first attack
ranges from one to 20 years; the frequency of attacks is highest between ages 15 and
35 and then decreases with age. A variable myopathy develops in at least 25% of
affected individuals and may result in a progressive fixed muscle weakness that
manifests at variable ages as exercise intolerance predominantly in the lower limbs.
It may occur independent of paralytic symptoms and may be the sole manifestation
of HOKPP. Individuals with HOKPP are at increased risk for pre- or post-anesthetic
weakness and may be at an increased risk for malignant hyperthermia though not as
great a risk as in individuals with true autosomal dominant malignant hyperthermia
susceptibility (MHS).