‘Hypokalemic i.e. flaccid muscle weakness involving two or more

‘Hypokalemic Periodic Paralysis (HPP)’ is characterized by muscle weakness secondary to low serum potassium levels. It may be primary in origin or there may be secondary causes like thyrotoxic periodic paralysis, renal or suprarenal causes or non-renal causes like gastroenteritis.  To study the etiology, clinical manifestations and outcome after therapy of patients with Hypokalemic Paralysis. Methodology: Study was conducted from January, 2016 to December, 2016. Patients fulfilling the diagnostic criteria for Hypokalemic Paralysis i.e. flaccid muscle weakness involving two or more limb muscles due to serum potassium < 3.

5 mmol/L and with no objective sensory signs were included in the study. Relevant investigations were done. Those with other causes of flaccid weakness or on diuretic therapy were excluded from the study. Data was analyzed using SPSS-20 version.   In our study, 14 patients out of a total of 18 (14/18 i.e. 77.78%) were male and 4/18 (22.

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22%) were female Male: Female ratio: 3.5:1. Mean age of onset of HPP in males (29.5+10.

14 yrs.) was lesser than that of females (41+10.8 yrs.) but this difference was statistically not significant (p<0.066). In the entire sample, there were 15/18 cases (83.

33%) of primary & 3/18 (16.67%) cases of secondary HPP 2/3 had thyrotoxic periodic paralysis & 1/3 had gastroenteritis. Furthermore, 12/18 patients (66.

66%) had symmetrical weakness (5 cases of paraparesis and all were male; 7 cases of quadriparesis: six males & one female) and 6/18 (33.33%) had asymmetrical weakness (two paraparesis: one male, one female; four quadriparesis: 2 males, 2 female). Statistically, no significant difference (p<0.709) seen in those with symmetrical vs. those with asymmetrical weakness. 7/18 (38.89%) cases had absent, 1/18 (5.55%) had diminished and 10/18 (55.

55%) cases had intact deep tendon reflexes. None of the cases had cranial, bulbar or respiratory involvement. Mean serum potassium of sample was 3.18+0.

5SD. Reduction in serum potassium was moderate (2.5-3.5mmol/L) in primary & severe (<2.5mmol/L) in secondary HPP. Those with quadriparesis had severe hypokalemia with mean serum potassium of 2.1 mmol/L.

Only 3/18 patients had concomitant magnesium deficiency. Patients given intravenous potassium replacement (except one with moderate hypokalemia & given oral replacement) recovered dramatically. Mean recovery time was 38.6+20.

3hrs. Recovery time in quadriparesis was about 24 hrs. and in paraparesis was 12 hrs. Only one patient with thyrotoxic periodic paralysis (TPP) & with severe serum potassium deficiency (0.

9meq/L) died due to cardiac arrhythmia. No atypical presentation was seen. Hypokalemic Periodic Paralysis has male preponderance. Age of onset of HPP is earlier in males than in females. Moreover, males are more prone to have symmetrical weakness. Asymmetrical weakness has almost an equal gender distribution.

Primary Hypokalemic Paralysis is more frequent than secondary. Thyrotoxic periodic paralysis is commonest cause of secondary periodic paralysis. Recovery time in quadriparesis is almost double the recovery time in paraparesis. Respiratory involvement is rare. HPP is an important differential in the diagnosis of acute flaccid muscle weakness.

It should be promptly addressed to prevent recurrence of paralysis.  Hypokalemic paralysis is one of the common cause of acute flaccid paralysis that is characterized by muscle weakness due to low serum potassium levels. 1 Hypokalemic paralysis can be primary or secondary. Hypokalemic periodic paralysis (HPP); a calcium channelopathy, which may be familial with autosomal dominant inheritance or sporadic 1.

Secondary causes of hypokalemic paralysis include renal causes (renal tubular acidosis, Gitelman syndrome, and primary hyperaldosteronism), endocrine causes (hyperthyroid periodic paralysis), and hypokalemia secondary to gastrointestinal losses (diarrhea). 2  Familial Hypokalemic paralysis is one of the most important causes of hypokalemic periodic paralysis among Caucasians 3 and thyrotoxic periodic paralysis is the leading cause of hypokalemic paralysis in Asian population with male to female ratio of approximately 70:1. 4 In Asian males hypokalemic periodic paralysis (PP) affects 2-10% of thyrotoxic patients. 4 Age of onset of hypokalemic periodic paralysis is mostly in first to second decade.

3 Hypokalemic periodic paralysis is the genetic disorder, caused by mutation in voltage gated calcium channel, CACNA1S gene on chromosome 1q. 1,3,4  Over the past decade, mutations in genes encoding three ion channels CACN1S,SCN4 and KCNJ2, have been identified and accounted for at least 70% of cases of PP. 1,2,4 Hypokalemic periodic paralysis is characterized by recurrent attacks of skeletal muscle weakness lasting minutes to hours with associated hypokalemia 2. HPP usually spares bulbar, ocular and respiratory muscles. 5 Hypokalemia is precipitated by stress, carbohydrate rich meal, infection, glucose infusion, hypothermia, anesthesia, strenuous exercise, metabolic alkalosis and steroids. 5 Thyrotoxic periodic paralysis is related to loss of function mutation of the skeletal muscle-specific inward rectifying K channel (Kir), Kir2.

6 is associated with decreased outward K efflux in skeletal muscle from either channeled mutation or hormone (insulin, adrenaline), leading to vicious circle of hypokalemia, which in turn leads to, sodium (Na) inactivation, skeletal muscle weakness or paralysis. 6 By successful treatment of thyrotoxicosis, symptoms of hypokalemic paralysis disappears. 6 Renal causes of hypokalemic paralysis are well known.

Renal tubular acidosis (RTA) is a recognized cause of severe hypokalemia.5 RTA and severe hypokalemia are associated with medullary sponge kidney, cystic kidney disease, and nephroclacinosis.7 Gastrointestinal potassium losses occurs due to heavy fluid losses through biliary tract or bowel are not uncommon 8 There is only one case report of hypokalemic paralysis caused by falciparum malaria published in Pakistan Armed Forces Medical Journal who recovered with parenteral quinine. 9 According to previous case studies in literature, some patients may go on to develop permanent proximal muscle weakness after years with periodic paralysis. 10   The mainstay of treatment in hypokalemic periodic paralysis is potassium replacement and acetazolamide, a carbonic anhydrase inhibitor. Hypokalemic paralysis is usually overlooked in patients with acute flaccid paralysis in emergency room.

  The present study is a retrospective chart review done over a period of one year, from January 2016 to December 2016. All patients admitted in Neurology ward in king Edward Medical University, with acute flaccid paralysis with hypokalemia (serum potassium<3.5) involving two or more limbs without sphincter and sensory disturbances were included in the study. Patients with other causes of acute flaccid weakness e.g. GBS, myasthenia crisis, and on diuretic therapy were precluded from the study. Medical history, previous episodes of similar weakness, hyperthyroidism, diarrhea, vomiting, renal disease, and drug intake were noted.

Any history of similar illness in the family and precipitating factors were enquired about and noted. Complete neurological examination including muscle tone, assessment of power using MRC Scale and deep tendon reflexes were noted. Any atypical presentation was also noted e.

g. facial, bulbar or respiratory muscles involvement. Labs, including Complete blood count (CBC), serum potassium, serum sodium, serum calcium, serum bicarbonate, thyroid profile (T3, T4, TSH) and ECG were obtained on the day of admission.  All patients were treated with potassium supplements – oral (500mg at 8 hour intervals) or IV (10meq/hour) depending upon their serum potassium levels and severity of clinical manifestations (extreme weakness). Patients with idiopathic periodic paralysis were started on acetazolamide (250mg tid) and dose was titrated according to the response. Patients were divided into groups, first with a primary idiopathic hypokalemic periodic paralysis and second group was secondary hypokalemic periodic paralysis (thyrotoxic periodic paralysis, renal tubular acidosis and gastroenteritis).  Continuous variables were expressed as mean ± standard deviation. A?P?value < 0.

05 was considered statistically significant, and a?P?value < 0.01 was considered statistically highly significant. All statistical analysis were conducted by SPSS version 21.  We enrolled 18 patients (mean age 35+15), 14 patients (77.

78%) were males. Male: Female ratio: 3.5:1. Mean age of onset of HPP in males was (29.5+10.

14 yrs.) as compared to females (41+10.8 yrs.), however this difference was statistically not significant (p<0.

066). Off these patients, 15 (83.33%) patients had primary HPP, while 3 (16.67%) cases had secondary HPP 2/3 with thyrotoxic periodic paralysis and 1/3 case was secondary to gastroenteritis.  Out of total 18 patients, symmetrical weakness was found in 12 (66.66%) patients with predominance in male patients (5 cases of paraparesis & all were male; 7 cases of quadriparesis: 6 male and one female). Six (33.33%) patients had asymmetrical weakness (two paraparesis: one male, one female; four Quadriparesis: 2 males, 2 female).

Statistically, no significant difference (p<0.709) was seen in those with symmetrical vs. asymmetrical weakness. Deep tendon reflexes were absent in 7 (38.89%) patients, diminished in one patient (5.

55%) and intact in remaining 10 (55.55%). None of the cases had cranial, bulbar or respiratory involvement. Mean serum potassium of sample was 3.18+0.

5SD.  Reduction in serum potassium was moderate (2.5-3.5mmol/L) in primary and severe (<2.

5mmol/L) in secondary HPP. Those with Quadriparesis had severe hypokalemia with mean serum potassium of 2.1 mmol/L. Concomitant magnesium deficiency was observed in 3/18 (17%) patients. All of these patients were treated with intravenous potassium replacement with dramatic recovery.

Mean recovery time was 38.6+20.3hrs.

Recovery time in patients with quadriparesis was about 24 hours and those with paraparesis was around 12 hours. Only one patient with thyrotoxic periodic paralysis (TPP) and with severe serum potassium deficiency (0.9meq/L) died due to cardiac arrhythmia. No atypical presentation was seen in the present studyThe hypokalemic paralysis of 15 patients from our study were primary idiopathic hypokalemic periodic paralysis.

Secondary hypokalemic paralysis occurred in three (16.67%) patients, thyrotoxic periodic paralysis (11.5%), and diarrhea (5.6%). The etiology of hypokalemic paralysis is varied across different ethnicity and geographical area.

1,3 In a study from North Korea, most of cases of hypokalemic paralysis were due to secondary hypokalemic paralysis and among secondary causes thyrotoxic periodic paralysis was found more frequent than other. 10   There was a significant difference in serum potassium levels in 2 groups, patients with secondary hypokalemic paralysis had more severe hypokalemia than primary hypokalemic periodic paralysis.  Despite the higher incidence of thyrotoxic periodic paralysis in males 11 in our study there was one male and one female with TPP.  Male preponderance of Thyroid periodic paralysis is hypothesized to be due to testosterone levels in blood. 6, 4 TPP is curable once acute thyrotoxicosis is resolved.  In hypokalemic periodic paralysis group 43 %( 7/16) had paraparesis, and 56% (9/16) had quadriparesis.  Typical hypokalemic periodic paralysis causes paraparesis.

Sensory system, bowel and bladder remains intact. 14  Overall the mean recovery time was 38.6+20.3hrs. Recovery time in patients with quadriparesis was about 24 hours and those with paraparesis was around 12 hours. Rarely does the thyrotoxic or hypokalemic periodic paralysis affects bulbar, ocular muscles or cranial nerves.

(2, 3, 7, 11) In previous studies need of ventilator support in hypokalemic and thyrotoxic periodic paralysis has been reported 11. None of our patients had any involvement of eye muscles or cranial nerves and neither needed ventilator support.  Other electrolytes abnormalities in thyrotoxic periodic paralysis has been reported, e.g. transient hypomagnesemia and hypophosphatemia which tends to resolve, once acute thyrotoxicosis settles 4, 7.  In our study one female patient with TPP had concomitant magnesium deficiency that was documented to be 0.

9meq/l and that patient died of cardiac arrhythmia.  There were increase occurrence of recurrent attacks in hypokalemic periodic paralysis than thyrotoxic periodic paralysis.   Treatment depends upon the severity of attack. Minor attacks with mild hypokalemia tend to resolve spontaneously. Management of hypokalemic periodic paralysis includes accurate diagnosis, optimum potassium replacement, choice of diuretic prophylaxis, identification of triggering factors, and managing the issues in pregnancy 12. Potassium chloride is the preferred salt given at 0.5- 1 mEq/kg for acute attacks.

13 Acetazolamide, or potassium sparing diuretics decreases attacks frequency and severity of attacks in future but of no use during acute attack hypokalemic paralysis. 14 Oral potassium in the form of solution, powder dissolved in water, or sustained release tablets has a role in its management 13. In cases where patients suffer from recurring morning attacks of paralysis, a trial of sustained release tablet taken at the time of sleep is warranted 15. In this study all patients responded well to intravenous potassium. Patients with moderate to severe hypokalemia require intravenous potassium.

16 There was only one patient in primary group in whom there was a spontaneous recovery. Potassium can be given orally for prophylaxis as well before strenuous exercise or carbohydrate load.15,14 During acute attack quicker results can be obtained by giving oral solution of potassium, response is seen within 30minutes after administration.17 total dose of potassium given should not exceed 240meq/l in 24 hours. Glucose or dextrose should not be used as solvent for oral solution instead mannitol is be considered as preferred solvent 13. Chronic administration of potassium supplements can lead to gastric irritation from locally high salt concentration. This can be counteracted with concomitant proton pump inhibitors.

  Acetazolamide is given as maintenance therapy. Carbonic anhydrase inhibitors are potassium wasting, occasional potassium supplements, even in the absence of attack is warranted. 18 If carbonic anhydrase inhibitors are not available then spironolactone is an option.

18 Management of thyrotoxic periodic paralysis depends on the adequate management of hyperthyroid state and correction of electrolyte abnormalities associated with it. 19 All three patients in secondary group were also given intravenous potassium and there was one mortality due to cardiac arrhythmia in TPP group. Intravenous (IV) replacement of potassium is done in TPP patient to prevent cardiopulmonary disturbances. However, with potassium replacement there is a danger of rebound hyperkalemia, usually after recovery of muscle weakness.

19 Beta adrenergic blockers e.g. propranolol is given to prevent rebound hyperkalemia and hasten recovery. 15, 19 Myopathy develops in at least 25% of affected individual and may lead to permanent muscle weakness later in life 14. No fixed, progressive proximal myopathy was found in our patients.

 Sample size of the study was small to comment on the most frequent group as a cause of hypokalemic paralysis in our population. Transtubular potassium concentrating gradient, potassium creatinine ratio, urinary potassium, Transtubular potassium concentrating gradient during paralytic attack was not done due to cost effectives and non-availability of these tests at our center. Hypokalemic paralysis should always be kept in mind in making differential diagnosis of acute flaccid paralysis. In all patients, serum electrolytes panel, ECG and thyroid profile should be done at admission in ICU. Immediate treatment should be started on diagnosis of hypokalemic paralysis either orally or intravenously.

Monitoring for cardiac arrhythmias should be done vigilantly.