hypokalemic periodic paralysis and steven johnson's syndrome case management

CASE MANAGEMENT ON HYPOKALEMIA ANDSTEVEN – JOHNSON’S SYNDROME

Christian Gallardo, MD1st Year Resident

Department of Internal MedicineUniversity of Perpetual Help

DALTA Medical Center

Objectives

To discuss the diagnosis, management and treatment of Hypokalemia

To discuss the pathophysiology and clinical features of Hypokalemic Periodic Paralysis and Renal Tubular Acidosis

To discuss Allopurinol as one of the causes of Steven Johnson’s Syndrome

General Data

S.A 31 year old Female Cavite City Roman Catholic Admitted for the first time

on July 30, 2009

Chief Complaint:

RASHES on FACE

History of Present Illness

Known Dyslipidemic and with Hyperuricemia recently diagnosed a month ago maintained on Simvastatin 20mg OD and Allopurinol 100mg OD.

1 Day PTA

•(+) Rashes on malar and frontal area, cheeks and neck area with periorbital edema•(+) Cough, non productive•(+) Generalized weakness of both upper and lower extremities•Patient took 1 tablet of Lagundi tablet which offered relief.


(-) Nausea, vomiting, LBM


Few Hours PTA

• Persistence of rashes on malar and frontal area, cheeks and neck area

• (+) ↑ periorbital edema and associated with swelling of the face

• (+) Cough• (+) ↑

generalizedweakness of upper and lower extremities

• (+) DOB• Admitted

(-) Nausea, vomiting, LBM

Past Medical History

Hypokalemia – Cavite City Medical Center (2002) Unrecalled potassium levels Consultation at SJDH – Thyroid

Function Test - normal levels No Maintenance given

Bronchial Asthma – Last attack - 7 years old, no exacerbations afterwards

No Allergies No Operations No Hypertension, No Diabetes

Family History

Hypokalemia – Father – with weakness episodes Had also cousins with hypokalemia on father

side Sister has also history of hypokalemia

maintained on potassium supplements

Hypertension – Maternal side Diabetes Mellitus – Maternal side Asthma – Maternal side Cervical Cancer and Breast Cancer –

Mother Leukemia – Maternal side Polycethemia Vera – Paternal side

Personal and Social History

Non smoker Non Alcoholic Beverage

drinker Works as a nurse

Review of Systems

General: (-) Weight Loss HEENT: (-) blurring of vision, (-)

sorethroat Cardiology: (-) chest pains, (-) PNDs, (-)

Orthopnea Gastroenterology: (-) abdominal pain, (-)

diarrhea, (-) constipation, (-) melena, (-) hematochazia

GUT: (-) dysuria, (-) oliguria (-)anuria Endocrinology: (-) polyuria, polydipsia,

polyphagia, Musculoskeletal: (-) myalgia Hematology: (-)easy brusability Neurology: (-) neuropathy, (-)seizures, (-)

headache

General: Conscious, coherent, Not in cardiorespiratory distress

VS: BP: 110/80 CR: 92 bpmRR: 20 cpm T: 36.7°C

Skin: (+)maculopapular rashes, non-scaling, non – blanching on malar region, cheeks, frontal area, neck, abdomen, trunks, back, upper and lower extremities

HEENT: Anicteric Sclerae, pale PC, (+) conjunctival erythema, (+) oral mucocutaneous lesion, (-) TPC, (-) NAD, (-) CLAD

Physical Examination

Physical Examination

Chest and Lungs: Symmetrical Chest Expansion, No retractions, (+) expiratory wheezes at both lung fields

Heart: Adynamic Precordium, PMI 5th ICS MCL, Normal Rate, Regular Rhythm, Normal S1 and S2, No S3 and S4, No Murmur.

Abdomen: Flat, Soft, NABS, Non-tender, No organomegaly

Extremities: No cyanosis, Full Pulses, No Edema

Neurologic Examination

Oriented to time, person and place Cranial Nerves:

I: can smell II: 2-3mm PERTL, Fundoscopy: (+) ROR,

Clear Media, Distinct Cup borders, CDR: 1:3, AVR: 2:3, No exudates, No Hemorrhage

III, IV, VI: Full EOM V: (+) bilateral corneal reflex, good

masseter tone VII: (-) facial asymmetry VIII: can hear IX, X: (+) gag Reflex XI: can equally shrug shoulder XII: no tongue deviation

Neurological Examination

(-) dysdiadochokinesia, (-) dysmetria, (-) Babinski (-) Brudzinski (-) Nuchal Rigidity

++1/5

++1/5 100%

3/53/5

++

++100%

100%

100%

++ ++

++++

3/5 3/5

1/5

1/5100%

100%

100%

100%

Salient Features

35 year Old Female 1 month History of Allopurinol use Cough DOB History of hypokalemia and asthma Stong family history of hypokalemia on

father and siblings Conjunctival erythema Maculopapular Rashes on the face,

abdomen, trunks and extremities Wheezes at both lung field Generalized weakness of Upper and Lower

Extremities

Working Impression:

Hypokalemia Probably Secondary to Renal Losses Hypokalemic Periodic

Paralysis vs Renal Tubular Acidosis

Hypersensitivity Vasculitis vs Steven-Johnson’s Syndrome Secondary to Allopurinol

Problem #1: Weakness of extremities S> Body Weakness:

Weakness of upper and lower extremities

(-) vomiting, headache and fever O> conscious, coherent, not in

respiratory distress

Laboratories1st HD 2nd HD 3rd HD

CBC

WBC 13.5 16.6 14.1

Hematocrit 0.46 0.43 0.43

Hemoglobin 146 128 139

Segmenters 0.77 0.74 0.58

Lymphocytes

0.17 0.15 0.28

Monocytes 0.04 0.09 0.09

Eosinophils 0.02 0.02 .05

Platelets Adequate

256 281

mmol/L1st HD 1st

HD9pm

2nd HD

Na 142 145

Cl 107

Mg 0.8

ABG

pH 7.32

pCO2 27.4

pO2 96.5

HCO3 14.0

S02 97.0

Simple Metabolic AcidosisWith adequate oxygenation

Admsn, 9 pm

1st HD, 8 am

1st HD, 2 pm

1st HD,

10pm

2nd HD

2nd HD

3rd HD

3rd HD, 9am

4th HD

00.5

11.5

22.5

33.5

44.5

5

22.3

2.8 2.7

3.9 3.94.3

3.4

4.2

Potassium

3/5 upper extremity2/5 lower extremity

Potassium Trend

KCL drip: PNSS 8O cc + 40 meqs KCL x

6 hrs

KCL drip: PNSS 8O cc + 40 meqs KCL x

6 hrsOral K durule 2

durule TIDNaHCO3 1 Tab TID

Mg Oxide


Spirinolactone 50mg/tab

then 25mg/tab BID

4 kalium Durule Q6hrsHypokalemia

2nd to1)

Hypokalemic Periodic Paralysis

2) RTA Type 1

2 kalium Durule TID


Spirinolactone 25mg/tab BID

Repeat Electrolytes OPD basis

Other LaboratoriesChemistry

Creatinine 94 mg/dL

Urine Potassium 34.4 mmol/L

Urine Osmolality 211mOsm/kg H2O

Urine Cl 68 mmol/L

Plasma Osmolality 212 mOsm/kg H20

Computation

Transtubular K+ Concentration Gradient (TTKG)

17.23

Anion Gap 21

Urine K (Uk) x Plasma Osmolality (Posm) TTKG = -------------------------------------------------------------- Plasma Potassium (Pk) x Urine Osmolality (Uosm)

Anion gap = Na- (Cl + HCO3)

Na 142 mmol/mL

Cl 107mmol/mL

HCO3 14 mmol/mL

Weiner D and Dingo C. Hypokalemia – Consequences, Causes and Correction. American Journal of Nephrology 1999. Vol 2:1179-1188

Primary (Familial) Autosomal dominant disorder Characterized by episodic attacks of

muscle weakness with concomitant hypokalemia (<3.5 mEq/L), which usually involves the four limbs.

Age at onset of paralytic crises - within the first or second decade.

The frequency of attacks is maximal between 15 and 35 yr of age and then decreases with age .

Weakness may be focal or generalized, usually sparing

facial and respiratory muscles, and lasting for hours

(occasionally days) withgradual resolution.

Hypokalemic Periodic Paralysis

The precipitating factors: - carbohydrate- or sodium-rich meals, - emotional stress, - and rest after exercise - exposure to cold - events associated with increase epinephrine or insulinSerum potassium are normal during asymptomatic periods

Nand B, Vohra S. Hypokalemic Periodic Paralysis: An Unusual Cause. Hospital Physician January 2003

Hypokalemic Periodic Paralysis Mutations in a calcium channel gene

(CACNA1S) or a sodium channel gene (SCN4A)

Majority of mutations in the CACNA1S gene located on chromosome 1q31-32.


Hypokalemic Periodic Paralysis The mechanism for depolarization-

induced attacks of weakness in HPP is not understood.

Missense mutations in the a1 subunit of the L-type calcium channel or less commonly in the voltage-gated sodium channel cause HPP.

Curiously, for both channel types the mutations occur in highly conserved arginine residues in the voltage-sensing segments. The calcium channel mutations cause a loss-of-function manifest as reduced current density and slower activation.

A study on fibres biopsied from a patient with the R528H calcium channel mutation detected a reduction in ATP-sensitive K current, which is more easily tied to depolarization with hypokalaemia and suggests a secondary channelopathy stemming from altered calcium homeostasis.

This observation does not readily explain the episodes of depolarization, weakness and hypokalaemia. In vitro, muscle fibres from patients with HypoPP depolarize in low K solution.

Venance S et al. The primary periodic paralyses: diagnosis, pathogenesis and treatment. Brain (2006), 129, 8–17

Renal Tubular Acidosis

Characterized by Metabolic acidosis, secondary to defects

in renal tubular reabsorption of bicarbonate (HCO3)

Urinary excretion of hydrogen (H+) Glomerular function is little or not

affected All forms of RTA present

hyperchloremic metabolic acidosis, with normal anion gapPereira P, Miranda D, Oliveira E. Molecular Pathophysiology of

Renal Tubular Acidosis. Current Genomics, 2009, 10, 51-59

Distal nephron net acid secretion is impaired. High urine pH, even in the presence of systemic acidosis. Incomplete Distal RTA

Often no metabolic acidosis and the blood bicarbonate concentration is normalDefect in renal acid excretion must be demonstrated by a failure to lower urine pH below 5.5 following an NH4Cl load or a modified furosemide test.

Acquired distal RTA Often secondary to autoimmune diseases, such as Sjogren’s syndrome.Hypokalaemia is less troublesome than in the acquired autoimmune form of distal RT.

But it can become symptomatic, especially if a thiazide diuretic is prescribed to reduce hypercalciuria.

Mechanism of Hypokalemia in Mg Deficiency Magnesium deficiency exacerbates

potassium wasting by increasing distal potassium secretion.

A decrease in intracellular magnesium, caused by magnesium deficiency, releases the magnesium-mediated inhibition of ROMK channels and increases potassium secretion.

•Magnesium deficiency alone, however, does not necessarily cause hypokalemia.•An increase in distal sodium delivery or elevated aldosterone levels may be required for exacerbating potassium wasting in magnesium deficiency.

Huang C and Kuo E. Mechanism of Hypokalemia in Magnesium Deficiency. J Am Soc Nephrol 18: 2649–2652, 2007

Hemorrhagic and crusted lesions affecting the lip, palate and buccal mucusa

Hemorrhagic and erythematous and vesicular lesion of generalised distribution

Problem #2: Rashes

Presence of erythema of the conjunctiva

1st HD 2nd HD 3rd HD 4th HD

Urine Culture 12,000 col/mL Diptheroids

CXR Normal

Hbs AG Non- reactive

Hbs AB Non-reactive

SGOT 41

SGPT 88

Problem #2: Rashes

Increase in rashes, Increase

Conjunctival

Redness CRP Negative

ESR 1 mm/hr

ANA Negative (1:40 dilution)Hydrocortisone IV

HydroxyzineMometasone

Furoate

Rashes:Etiology

- Drug induced?

Allopurinol-Induced Dress Syndrome

Hypersensitivity Vasculitis

Steven Johnson’s Syndrome

1st HD

CBC

WBC 13.5

Hematocrit 0.46

Hemoglobin 146

Segmenters 0.77

Lymphocytes

0.17

Monocytes 0.04

Eosinophils 0.02

Platelets Adequate

Describes the association of drug (allopurinol) together with eosinophilia and systemic symptoms (hepatitis and progressive renal failure)

Drug Rash with

Eosinophilia and Systemic

Syndrome

Allopurinol-Induced DRESS Syndrome

Markel, A. Allopurinol-Induced Dress Syndrome . Internal Medicine American Journal 2005. Vol 7: 656-660.

Skin rash, fever, lymph node enlargement and single or multiple organ involvementSkin: maculopapular eruption and facial edemaStarts 2-6 week after commencement of medication

Allopurinol Dress Syndrome Prevelence: 2% of taking drug

Criteria

A documented intake of Allopurinol

Lack of exposure to a different drug causing a similar picture

Presence of at least 2 major criteria and 1 minor criteria• Major Criteria

- Worsening renal function - Acute hepatocellular injury - Rash, manifesting by toxic epidermal necrolysis, erythema multiforme, diffuse maculopapular rash or exfoliative dermatitis•Minor Criteria include fever, leukocytosis and eosinophila

Markel, A. Allopurinol-Induced Dress Syndrome . Internal Medicine American Journal 2005. Vol 7: 656-660.


Problem #2: Rashes


Conjunctival

Redness

Skin Biopsy -

contemplated

2nd HD

CBC

WBC 16.6

Hematocrit 0.43

Hemoglobin 128

Segmenters 0.74

Lymphocytes

0.15

Monocytes 0.09

Eosinophils 0.02

Platelets 256

Mild clearing of rashes

DesloratadineButamirate

Citrate

Rashes:Etiology

- Drug induced?



Laboratories

CRP Negative

ESR 1 mm/hr

ANA Negative (1:40 dilution)

Urine Culture 12,000 col/mL Diptheroids

CXR Normal

Hbs AG Non- reactive

Hbs AB Non-reactive

SGOT 41

SGPT 88

Hypersensitivity Vasculitis American College of Rheumatology

1990 Criteria for the Classification of

Hypersensitivity Vasculitis 3+ present, sesitivity 71%,

specificity 84%

Ruddy et al. Kelly’s Textbook of Rheumatology 6th Edition 2001. Volume 2:1197

• Age > 16 y/o• Possible offending drug• Palpable Purpura• Maculopapular rash• Skin Lesion biopsy showing granulocytes (neutrophils, eosinophils or both) in a privascular or extravascular location around arteriole or venule


Clinical Manifestation Palpable purpura, fever, urticaria,

arthralgia, lymphadenopathy Begin 7-10 days after antigen exposure Includes glomerulonephritis, instertitial

nephritis, hepatocelluar injury and GI, CNS or pulmonary vasculitis

Ruddy et al. Kelly’s Textbook of Rheumatology 6th Edition 2001. Volume 2:1197

Diagnosis:

Biopsy


Problem #2: Rashes


Conjunctival

Redness

Clearing of rashes

BetamethasonePrednisone 15mg

TIDPetroleum Jelly

TID

Rashes:Etiology

- Drug induced: Allopurinol


3rd HD

CBC

WBC 14.1

Hematocrit 0.43

Hemoglobin 139

Segmenters 0.58

Lymphocytes

0.28

Monocytes 0.09

Eosinophils .05

Platelets 281

Steven Johnson’s Syndrome(SJS) Life treatening, bullous,

mucocutaneous disease, generally considerd to be immune-medicated reactions to drugs. Epidermal necrosis, extensive

detachment to the epidermis, erosions of mucous membranes and severe constitutional syndrome

Halevy S, Ghislain PD, Mockenhaupt M et al. Allopurinol is the most common cause of SJS and TEN in Europe and Israel. Journal of American Academy of

Dermatology 2008:58:25-32.

SJS (<10% BSA)Toxic epidermal necrolysis (TEN) (>30% BSA)

Steven Johnsons Syndrome(SJS) European Case-Control Surveillance

of severe cutaneous adverse drug reactions (EuroSCAR) A daily dose of 200mg or more of

allopurinol was associated with increased risk for SJS and TEN compared with lower daily doses.

Risk: Recent users ≤ 8 weeks

Halevy S, Ghislain PD, Mockenhaupt M et al. Allopurinol is the most common cause of SJS and TEN in Europe and Israel. Journal of American Academy of

Dermatology 2008:58:25-32.

Singapore and Taiwan studies: 28% of SJS due to allopurinol

Final Diagnosis:

Hypokalemia Secondary to Hypokalemic Periodic Paralysis

Steven Johnson’s Syndrome Drug Induced (Allopurinol)

Hypokalemia

The average daily potassium intake: 70 mEq.

90% of potassium excreted in the urine and the vast majority of the remainder in the stool.

Most potassium is present in the intracellular space.

Weiner D and Dingo C. Hypokalemia – Caonsequences, Causes and Correction. American Journal of Nephology 1999. Vol 2:1179-1188

Hypokalemia

Potassium is freely filtered at the glomerulus, followed by reabsorption of approximately 85% by the proximal tubule and the loop of Henle.

Weiner D and Dingo C. Hypokalemia – Caonsequences, Causes and Correction. American Journal of Nephology 1999. Vol 2:1179-1188

↓ Serum K from 3.5 to 3.0 mEq/LTotal body potassium deficit = 100 to 300 mEq,

↓ 2.0 mEq/L Total body deficit = 600 to 800 mEq.

Reabsorbtion and Secretion

Weiner D and Dingo C. Hypokalemia – Consequences, Causes and Correction. American Journal of Nephrology 1999. Vol 2:1179-1188

Principal cell is the most numerous cell, comprising 60 to 70% of the CCD, and is believed to be responsible for potassium secretion.

CCD A- and B-type intercalated cells (A cell and B cell), which comprise the remainder of the CCD, are modeled to reabsorb luminal potassium.

Other Causes of Hypokalemia

Manifestation of Hypokalemia Symptoms generally do not become

manifest until the serum is below 3.0 meq/L

Severe muscle weakness or paralysis – occur usually < 2.5 meq/L Lower extremities progresses to the

trunk and upper extremities

Rose B, Sterns R, Post T. Clinical Manifestation and Treatment of Hypokalemia. UpToDate 2009.

Other clinical manifestations:Respiratory muscle weakness, ileus, distention, anorexia, nausea, vomiting, cramps and tetany

Cardiac Arrythmias and ECG Abnormalities Premature atrial beat and ventricular

beat, sinus beat, paroxysmal atrial tachycardia, atrioventricular block and ventricular tachycardia.


Depression of the ST segment, decrease in the amplitude of the T wave and increase in the amplitude of U waves which occur at the end of the T wave.U waves in the lateral precordial leads V4 to V6

Manifestation of Hypokalemia Rhabdomyolysis

K<2.5meq/L can lead to rhabdomyolysis, muscle cramps and myoglobinuria

Renal Abnormalities (reversible) Urinary concentrating abilities, increased

renal ammonia production due to intracellular acidosis, increased renal bicarbonate reabsorbtion and hypokalemic nephropathy


Correction of Hypokalemia

There is no strict correlation between the serum K concentration and total body K stores – can only be approximated in chronic hypokalemia

K deficit of 200-400 meq Lower the serum K by 1 meq/L


Transcellular Potassium Redistribution

•This estimation mentioned does not apply

• Diabetic ketoacidosis- may have normal plasma potassium levels despite losses due to insulin and fluids

Correction of Hypokalemia (Oral) K preparations:

Intravenous or oral potassium is generally preferred over K citrate or K bicarbonate Metabolic alkalosis due to diuretic therapy,

vomiting, hyperaldosterism K citrate or K bicarbonate

Hypokalemia and metabolic acidosis


Oral therapy is usually preferred over parenteral replacement of

potassium

Correction of Hypokalemia (IV) Intravenous administration

Who cannot eat Had severe symptomatic hypokalemia

20-40 meq/L – peripheral vein More concentrated solutions can be

infused into large veins in severe symptomatic hypokalemia


Correction of Hypokalemia (IV) Maximum recommended rate (IV):

10-20meq/hr However, 40-100meq/hr – patients with

paralysis of life threatening arrhythmias Should be prepared as 10-20 meqs of K

in 100ml of fluid to avoid accidental administration of IV K.

Careful monitoring of physiologic effects of severe hypokalemia is essential


Correction of Hypokalemia (IV) Saline rather than dextrose is

recommended Dextrose can lead to transient 0.2-1.4

meq/L reduction in the serum K, particularly if only 20 meq/L of KCl

Can induce arrhythmias in susceptible patients Mediated by dextrose-stimulated release

of insulin and enhancing the activity of cellular NA-K-ATPase pump



Mild to moderate hypokalemia (3.0-3.5 meq/L) Directed toward replacing the lost

potassium and treating the underlying disorder (vomiting or diarrhea).

10-20 KCL 2-4x/day (20-80meqs/day) Sequential monitoring of the serum K



Severe Hypokalemia (<2.5 to 3.0 meq/L or symptomatic) Potassium must be given more rapidly to

patients with severe hypokalemia Caution must be exercise

When treated, will tend to drive K into cells and worsen hypokalemia


• Serum K can rise acutely by as much as 1 – 1.5 meq/L after oral dose of 40-60meq and by 2.5 to 3.5 meq/L after 135-160 meq

• Larger doses - gastric irritation but is transient

• 2 meq/L = 400-800 meqs K deficit• Oral: 40-60 meqs 3-4X/day until serum K above 3.0 to 3.5 or symptoms resolve and thereafter reduce dose and frequency


For chronic replacement – serum K should be measured 3-4x a month

Oral KCl preparation salt substitutes sprinkled on food (50-65meqs KCl per level teaspoon)


Summary

HPP is a rare disorder of uncertain cause characterized by potentially fatal episodes of muscle weakness or paralysis.

RTA present hyperchloremic metabolic acidosis, with normal anion gap.

SJS is a life treatening, bullous, mucocutaneous disease, generally considerd to be immune-medicated reactions to drugs.

Summary

Oral therapy is usually preferred over parenteral replacement of potassium

Mild to moderate hypokalemia (3.0-3.5 meq/L) 10-20 KCL 2-4x/day (20-80meqs/day)

Severe Hypokalemia (<2.5 to 3.0 meq/L or symptomatic) Potassium must be given more rapidly to

patients with severe hypokalemia

THANK YOU.

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