Periodic paralysis

Dr Abdullah Ansari
PG-2 (Medicine)
AMU ALIGARH

A general approach to periodic paralysis....
(including hypokalemic periodic paralysis and thyrotoxic periodic paralysis, and other “Channelopathies” or “Membranopathies)

Pathophysiology
Epidemiology
Primary or familial periodic paralysis
Secondary periodic paralysis
Conventional classification of periodic paralysis
Classification of primary periodic paralysis based on ion-channel abnormalities

Clinical approach to a case of periodic paralysis
History of muscle weakness
Age of onset
Family history
Timing
Intensity
History of administration of certain drugs
Clinical examination
Differential Diagnosis

Laboratory investigations
Serum K+
CPK and serum myoglobin
ECG
EMG
Nerve conduction studies
Provocative Testing
Muscle biopsy

Treatment
Prognosis

1. PERIODIC PARALYSIS Dr Abdullah Ansari PG-2 (Medicine) AMU ALIGARH

2. 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

3. 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

4. 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%

5. Primary or familial periodic paralysis Hereditary A single gene mutation Ca ++ , Na + or K + chloride channels abnormalities on muscle membrane “ Channelopathies ” or “ Membranopathies ”

6. Secondary periodic paralysis A demonstrably known causes Serum potassium abnormal even in inter-ictal phase

7. Conventional classification of periodic paralysis Primary or familial periodic paralysis : Hypokalemic periodic paralysis Hyperkalemic periodic paralysis Normokalemic periodic paralysis All have autosomal dominant inheritance .

8. Secondary periodic paralysis: 1. Hypokalemic periodic paralysis. Thyrotoxicosis Thiazide or loop-diuretic induced Potassium losing nephropathy Drug-induced: gentamicin, carbenicillin , amphotericin-B, alcohol Primary or secondary hyperaldosteronism GI potassium loss

9. 2 . Hyperkalemic periodic paralysis Chronic kidney disease High dose of ACE- i K + supplements with K + s paring diuretics and/or ACE- i Andersen Tawil syndrome Paramyotonia congenita 3. Potassium-aggravated myotonia

10. Classification of primary periodic paralysis based on ion-channel abnormalities Disease 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 ,, ,,

11. Clinical approach to a case of periodic paralysis Detailed history Clinical examination Simple laboratory investigations ECG and EMG Muscle biopsy

12. 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

13. 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

14. 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

15. Family history Usually a strong family history in primary PP 33 % cases are sporadic

16. 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

17. 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

18. 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

19. Clinical examination Most patients present during the inter-ictal period No positive physical finding in the primary PP

20. 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

21. 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

22. 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) Cold Rest following exercise Alcohol Infection Emotional stress Trauma Menstrual period Rarely severe Perioral and limb paresthesias Myotonia frequent Occasional pseudo-hypertrophy of muscles Hypo- kalemic periodic paralyses Childhood to third decade Majority of cases before 16 years Few hours to almost a week Typically no longer than 72 hr Early morning attacks after previous day physical activity High-carbohydrate meal , alcohol Cold, change in barometric pressure or humidity Fever , URTI Lack of sleep, fatigue Menstrual cycle Severe Complete paralysis Occasional myotonic lid lag Myotonia between attacks rare Unilateral, partial, monomelic Fixed muscle weakness late in disease

23. Syndrome Age of onset Duration of attack Precipitating factors Severity of attacks Associations Potassium- associated myotonia First decade No weakness Cold Rest 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 muscles Paradoxical myotonia Fixed weakness rare Thyrotoxic periodic paralyses Third and fourth decades Few hours to 7 days Same as hypokalemic PP Hyper- insulinemia Same as hypokalemic PP Fixed muscle weakness may develop Hypokalemia during attacks

24. 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

25. Differential Diagnosis of Secondary Periodic Paralysis Hypokalemic 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

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

27. Laboratory investigations

28. 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

29. “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”

30. 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

31. CPK and serum myoglobin Serum CPK is high in primary PP during or just after attack Serum myoglobin may be high

32. ECG ECG to corelate the serum potassium levels In Andersen Tawil syndrome, ECG and Holter reveal prolonged QT interval and ventricular arrhythmias

33. 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)

34. Nerve conduction studies Compound muscle action potential amplitude declines during attacks Sensory nerve conduction study usually normal

35. 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

36. Hypokalemic periodic paralysis Oral glucose loading test Intravenous glucose challenge Intra-arterial epinephrine test Hyperkalemic periodic paralyses Oral Potassium chloride test

37. 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

38. Treatment

39. 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

40. 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 2 nd line drugs

41. 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

42. 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

43. 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

44. 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

45. 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

46. 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 affected Hypokalemic 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

47. 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

48. Thank you