PERIODIC PARALYSIS

Dr Abdullah AnsariPG-2 (Medicine)AMU ALIGARH

Introduction…

A group of disorders of different etiologies with • episodic, short-lived, and hypo-reflexic skeletal muscle weakness• with or without myotonia • without sensory deficit• without loss of consciousness

Pathophysiology

• The physiologic basis of flaccid weakness is inexcitability of the muscle membrane• Defects in the ion channels that allows ions to leak in or out of the

muscle cell altering its polarization• Alteration potassium level is not the principal defect, the altered

potassium metabolism is a result of the PP

Epidemiology

• The frequencies of hyperkalemic PP, paramyotonia congenita, and potassium-aggravated myotonias are not known• Hypokalemic PP has a prevalence of 1 per 100,000• Thyrotoxic PP more common in males (85%) of Asian descent with a

frequency of 2%

Primary or familial periodic paralysis

• Hereditary• A single gene mutation• Ca++, Na+or K+ chloride channels abnormalities on muscle membrane• “Channelopathies” or “Membranopathies”

Secondary periodic paralysis

• A demonstrably known causes • Serum potassium abnormal even in inter-ictal phase

Conventional classification of periodic paralysisPrimary or familial periodic paralysis:

1. Hypokalemic periodic paralysis2. Hyperkalemic periodic paralysis3. Normokalemic periodic paralysis

All have autosomal dominant inheritance.

Secondary periodic paralysis:

1. Hypokalemic periodic paralysis.a. Thyrotoxicosisb. Thiazide or loop-diuretic inducedc. Potassium losing nephropathyd. Drug-induced: gentamicin, carbenicillin, amphotericin-B, alcohole. Primary or secondary hyperaldosteronismf. GI potassium loss

2. Hyperkalemic periodic paralysisa. Chronic kidney diseaseb. High dose of ACE-ic. K+ supplements with K+sparing diuretics and/or ACE-id. Andersen Tawil syndromee. Paramyotonia congenita

3. Potassium-aggravated myotonia

Classification of primary periodic paralysis based on ion-channel abnormalitiesDisease Gene Protein Inheritance Mutuation

Hyperkalemic PP SCN4A Nav1.4 Dominant Gain

Normokalemic PP ,, ,, ,,

Paramyotonia congenita ,, ,, ,,

Hypokalemic PP Type II ,, ,, ,,

Hypokalemic PP Type I CALCL 1A3 Cav1.1 ,, ,,

Thyrotoxic PP KCNJ18 Kir2.6 ,, Loss

Andersen-Tawil syndrome KCNJ2 Kir2.1 ,, ,,

Clinical approach to a case of periodic paralysis

• Detailed history• Clinical examination• Simple laboratory investigations• ECG and EMG• Muscle biopsy

History of muscle weakness

• Episodic short-lived paralysis of one, two, or all four limbs• Without loss of consciousness or sphincter dysfunction• Weakness may start proximally and spread distally• Paralysis may last for hours to several days• Frequency daily to yearly

• Strength normal in between attacks• Fixed weakness may develop later in some forms• In rare cases, respiratory muscles and cranial musculature may be

involved• Fatal if not recognized and treated promptly

Age of onset

• Early childhood : hyperkalemic PP and paramyotonia congenita• Soon after puberty but earlier than 25-30 yr : hypokalemic PP• after 25 yr : secondary periodic paralysis

Family history

• Usually a strong family history in primary PP• 33% cases are sporadic

Timing

• Periodic paralysis occurs typically on waking from sleep or on rest after exercise• It never occurs in the midst of vigorous exercise• This differentiates it from myasthenia gravis

Intensity

• Attacks – mild or severe• During mild attacks, feeling of tiredness and fatigue of muscles that

usually disappears in an hour• In severe attacks, complete immobility of affected limbs

History of administration of certain drugs

• Diuretics, ACE-i, ARBs, gentamicin, carbenicillin, etc• History of gastroenteritis, oliguria or anuria, severe PPH, or septic

abortion be asked

Clinical examination

• Most patients present during the inter-ictal period• No positive physical finding in the primary PP

During paralytic attacks• Muscles are flaccid • Tendon jerks are absent• Babinski’s sign is negative• There is no cloudiness of sensorium• No sensory deficit is present• Myotonia can be elicited in few cases of paramyotonia congenita with

hyperkalemic periodic paralysis• Myotonia may be marked in eyelids in the hyperkalemic type

• In secondary PP, features of causative disorders like thyrotoxicosis, CKD, diabetic nephropathy, acute glomerulonephritis, or ATN may be present• In thyrotoxic PP, the initial attack may occur before, during, or soon

after diagnosis of thyrotoxicosis

Syndrome Age of onset Duration of attack Precipitating factors Severity of attacks Associations

Hyper-kalemic periodic paralyses

First decade of life

Few minutes to less than 2 h (mostly less than 1 h)

Low carbohydrate intake (fasting)ColdRest following exerciseAlcoholInfectionEmotional stressTraumaMenstrual period

Rarely severe Perioral and limb paresthesiasMyotonia frequentOccasional pseudo-hypertrophy of muscles

Hypo-kalemic periodic paralyses

Childhood to third decadeMajority of cases before 16 years

Few hours to almost a weekTypically no longer than 72 hr

Early morning attacks after previous day physical activityHigh-carbohydrate meal, alcoholCold, change in barometric pressure or humidityFever, URTILack of sleep,fatigueMenstrual cycle

SevereComplete paralysis

Occasional myotonic lid lagMyotonia between attacks rareUnilateral, partial, monomelicFixed muscle weakness late in disease

Syndrome Age of onset Duration of attack Precipitating factors

Severity of attacks Associations

Potassium- associated myotonia

First decade No weakness ColdRest after exercise

Attacks of stiffness can be mild to severe

Muscle hypertrophy

Para-myotonia congenita

First decade 2-24 hr Cold Rarely severe Pseudo-hypertrophy of musclesParadoxical myotoniaFixed weakness rare

Thyrotoxic periodic paralyses

Third and fourth decades

Few hours to 7 days Same as hypokalemic PPHyper-insulinemia

Same as hypokalemic PP

Fixed muscle weakness may developHypokalemia during attacks

Andersen-Tawil syndrome

• Autosomal dominant• Onset in early childhood• Triad of dysmorphic features, periodic paralysis, and cardiac arrhythmias• Patients may have short stature, hypertelorism, low-set ears,

micrognathia, fifth finger clinodactyly, and scoliosis• Episodic weakness lasting a few to several hours• Not associated with myotonia• Prolonged QT interval and ventricular arrhythmias are the most common

cardiac manifestations

Differential Diagnosis of Secondary Periodic ParalysisHypokalemic

• Urinary potassium wasting• Hyperaldosteronism• Bartter syndrome• Alcohol• Drugs - Amphotericin B, barium• Renal tubular acidosis• GI potassium-wasting

Hyperkalemic

• Addison disease• Chronic renal failure• Hyporeninemic• Hypoaldosteronism• Ileostomy with tight stoma• Potassium load• Potassium-sparing diuretics

Differential Diagnosis of Other Entities Causing Acute Generalized Weakness• Transient Ischemic Attacks• Sleep attacks• Myelopathy• Myasthenia gravis• Acute inflammatory demyelinating polyneuropathy• Porphyria• Toxins

Laboratory investigations

Serum K+

• The most important investigation• Serum K+ in between attacks• Secondary PP : abnormal• Primary PP : usually normal

• During attack, serum K+ may be high, low, or in upper or lower range of normal• Random testing for serum K+ may show periodic fluctuation in

normokalaemic PP

“Abnormal serum potassium level in absence of any other obvious cause in a patient with history of episodic short lived paralysis of skeletal muscle is almost diagnostic of periodic paralysis”

Cont….

• Urinalysis, blood sugar, blood urea, serum creatinine, T3, T4 and TSH to exclude diabetic nephropathy, chronic or acute renal failure, and thyrotoxicosis • Phosphorus and magnesium may be low in secondary hypokalaemic

periodic paralysis

CPK and serum myoglobin

• Serum CPK is high in primary PP during or just after attack• Serum myoglobin may be high

ECG

• ECG to corelate the serum potassium levels• In Andersen Tawil syndrome, ECG and Holter reveal prolonged QT

interval and ventricular arrhythmias

EMG

• During attacks, EMG shows electrical silence• In between attacks, there may be fibrillation and complex repetitive

discharges, increased by cold and decreased by exercise (in hypokalaemic PP)

Nerve conduction studies

• Compound muscle action potential amplitude declines during attacks• Sensory nerve conduction study usually normal

Provocative Testing

General precautions• physician presence during testing• performance in an intensive care setting• avoidance in potassium disturbances, diabetes mellitus, or renal or

cardiac dysfunction• close monitoring of ECG• capability for rapid electrolyte and glucose correction

Hypokalemic periodic paralysis• Oral glucose loading test• Intravenous glucose challenge• Intra-arterial epinephrine test

Hyperkalemic periodic paralyses• Oral Potassium chloride test

Muscle Biopsy

• The most characteristic abnormality is the presence of vacuoles in the muscle fibers• More marked in hypokalemic PP • Signs of myopathy include muscle fiber size variability, split fibers, and

internal nuclei• Muscle fiber atrophy in clinically affected muscles • Tubular aggregates in some hypoPP, subsarcolemmal in location• Muscle fiber necrosis rare

Treatment

Hypokalemic Periodic Paralysis

• Acute paralysis : Oral KCl (0.2–0.4 mmol/kg) every 30 min• Muscle strength and ECG should be monitored• IV therapy rarely required (e.g., when swallowing problems or

vomiting is present)• Avoid potassium in dextrose solution • Mannitol is the preferred vehicle for IV potassium

• The long-term goal is to avoid attacks, may reduce late-onset, fixed weakness• For prophylaxis, dichlorphenamide 50-100 mg BD or Acetazolamide

125–1000 mg/d in divided doses• If attacks persist, oral KCl should be added• Triamterene 25–100 mg/d or spironolactone 25–100 mg/d are 2nd line

drugs

Thyrotoxic periodic paralysis

• In acute attacks, potassium restore muscle strength and prevent complications• Caution advised as the total amount of potassium in the body is not

decreased and potassium levels may overshoot ("rebound hyperkalemia")• Slow infusions of potassium therefore recommended

• Symptoms typically respond to propranolol• Treatment of thyrotoxicosis usually leads to resolution of the paralytic

attacks• Dichlorphenamide 50-100 mg BD or propranolol in doses of 20-40 mg

BD control recurrent attacks

Hyperkalemic periodic paralyses

• Attacks mild and rarely require treatment• In severe attacks, therapeutic measures that reduce hyperkalemia are

utilized• Continuous ECG monitoring during the treatment• Thiazide diuretics and carbonic anhydrase inhibitors for prophylaxis

Paramyotonia congenita• Weakness uncommon, treatment aimed at reducing myotonia• Thiazide diuretics (chlorothiazide 250–1000 mg/d) and mexiletine

(slowly increase dose from 450 mg/d)

Andersen-Tawil syndrome• Acetazolamide may decrease attack frequency and severity• Implantation of a cardiac defibrillator has rarely been performed

Diet

• Hypokalemic periodic paralyses: Low-carbohydrate and low-sodium diet may decrease frequency of attacks • Hyperkalemic periodic paralyses: Glucose-containing candy or

carbohydrate diet with low potassium may improve the weakness

Prognosis Hyperkalemic periodic paralyses and paramyotonia congenital• When not associated with weakness, usually do not interfere with ability to

work• Myotonia may require treatment• Life expectancy not known to be affectedHypokalemic periodic paralyses• Untreated patients may experience fixed proximal weakness, which may

interfere with activities• Several deaths reported, related to aspiration pneumonia or inability to

clear secretions

Summary

• PP characterized by episodic short-lived paralysis of skeletal muscles• Idiopathic (primary or familial PP) or due to identifiable causes

(secondary PP)• Serum potassium level abnormal during attacks• Both these groups are eminently treatable• Specific treatment for underlying disorders in secondary PP must be

instituted

Thank you