HYPERKALEMIC PP VS HYPOKALEMIC PERODIC PARALYSIS

OUTLINE

• Causes Of Primary Periodic paralysis

• Causes Of Secondary Periodic paralysis

• PRESENTATION OF HYPERKALEMIC PP

• COMPARISON BETWEEN Hyper PP Vs Hypo PP

• Primary Periodic paralysis

• Secondary Periodic paralysis

Causes of Primary Periodic paralysis

– Hypokalemic (CACNA1S/ SCN4A)

– Hyperkalemic (SCN4A)

– Anderson Tawil syndrome (KCNJ2)

3

Periodic paralysis

Secondary Periodic Paralysis

• Hypokalemic:– Thyrotoxic periodic

paralysis– hyperaldosteronism– RTA– villous adenoma– cocaine binge– diuretics, licorice,

steroids, ETOH

• Hyperkalemic(k>5.5)– hyporeninemic

hypoaldosteronism(DM/CKD) (ie, GFR or ≤ 20 mL/min).

– type IV renal tubular acidosis (RTA)

– AKI/Metabolic acidosis– High oral K, DRUGS– chronic heparin therapy– Rhabdomyolysis– Adrenal insufficiency

4

MACHINE

HYPERKALEMIC PERIODIC PARALYSIS

MUTATED GENE SCN4A

CHROMOSOME 17q

DEFECTIVE CHANNEL SODIUM

MODE OF INHERITENCE

AUTOSOMAL DOMINANT

Hyperkalemic Periodic Paralysis

• term hyperkalemic is misleading since patients are often normokalemic during attacks.

• Onset first decade• M : F 1:1• Attacks are brief and mild, usually lasting 30

minutes to 4 hours.• Weakness affects proximal muscles, sparing

bulbar muscles. • Attacks are precipitated by rest following exercise

and fasting.

• In a variant of this disorder, the predominant symptom is myotonia without weakness (potassium-aggravated myotonia).

• The symptoms are aggravated by cold, and myotonia makes the muscles stiff and painful.

• Clinically apparent myotonia is seen less than 20% of patients, but electrical myotonia may be found in 50-75%.

Pathophysiology

In hyperKPP, Na+ channels fail to inactivate and prolonged openings and depolarization result.

Increased extracellular K+ levels worsen the inactivation of Na+ channels

INVESTIGATIONS

• Potassium may be slightly elevated but may also be normal during an attack.

• NCV reduced motor amplitudes and In between attacks of weakness, the conduction studies are normal.

• EMG may be silent in very weak muscles. • often demonstrate myotonic discharges during

and between attacks.• Muscle biopsy shows vacuoles that are smaller,

less numerous, and more peripheral compared to the hypokalemic form or tubular aggregates.

TREATMENT

• For patients with frequent attacks, acetazolamide (125–1000 mg/d) is helpful.

• mexiletine is helpful in patients with significant myotonia.

HYPOKALEMIC HYPERKALEMIC

PREVELANCE 1:100,000 1:200,000

AGE OF ONSET FIRST AND SECOND DECADE OF LIFE

FIRST DECADE

SYMPTOMS DURING ATTACKS

ACUTE ONSELT FLACCID PARALYSISPROXIMAL >>> DISTAL

WEAKNESS OF PROXIMAL MUSCLE,SPARING BULBAR MUSCLE

SYMPTOMS BETWEEN ATTACKS

ASYMPTOMATIC ASYMPTOMATIC

FREQUENCY Daily to yearly May be 2–3/d

DURATION 2–12 h From 1–2 h to >1 d

HYPOKALEMIC HYPERKALEMIC

Effect of muscle cooling

No change Increased myotonia

TRIGGERS HIGH CARBOHYDRATE,HIGH SALT,DRUGS-BETAAGONISTS, INSULINREST FOLLOWING PROLONGED EXERCISE

REST AFTER EXERCISESTRESSFATIGUEFOOD HIGH IN POTASSIUMALCOHOLINFECTION

POSTASSIUM SUPPLEMENTATION

TREATMENT PROVOCATIVE TEST

SERUM POTASSIUM CONCENTRATION

LOW HIGH, NORMAL

ECG HYPOKALEMIC CHANGES

HYPERKALEMIC CHANGES CHANGES

MUSCLE BIOPSY SINGLE OR MULTIPLE CENTRALLY PLACED VACUOLES

SMALLER, LESS NUMEROUS PERIPHERALLY PLACED VACUOLES

NERVE CONDUCTION TEST REDUCED AMPLITUDE OF ACTION POTENTIAL

REDUCED AMPLITUDE OF ACTION POTENTIAL

ELECTROMYGRAPHY ELECTRICALLY SILENT ELECTRICALLY SILENTMYOTONIC DISCHARGE BETWEEN ATTACKS

GENETIC STUDY CALCL1A3, SCN4A SCN4A

TREATMENT MILD SUSTAINED EXERCISELOW POTASSIUM DIETBETA AGONISTTHIAZIDESHIGH SUGAR LOADCALCIUM GLUCONATE

PROPHYLAXIS ACETAZOLAMIDE , MEXILETINE(125-1000 Mg)

ACUTE ONSET WEAKNESS –AIDP VS HYPOKALEMIC PERODIC PARALYSIS

OUTLINE

• DIFFERENTIAL DIAGNOSIS OF AIDP

• PRESENTATON OF AIDP

• CAUSES OF PERIODIC PARALYSIS

• PRESENTATION OF HYPOKALEMIC PP

• COMPARISON BETWEEN AIDP VsHypo PP

DIFFERENTIAL DIAGNOSIS OF AIDP

PERIPHERAL NEUROPATHIES Toxic • Vincristine• Glue sniffing• Heavy metal• Organophosphate pesticidesInfections • HIV• Diphtheria• Lyme diseaseInborn errors of metabolism • Leigh disease (Subacute Necrotizing

Encephalomyelopathy)• Tangier disease (Familial alpha-

lipoprotein deficiency)• PorphyriaCritical illness: polyneuropathy

SPINAL CORD LESIONS Acute transverse myelitisEpidural abscessTumorsPoliomyelitisVascular malformationsCord infarctionCord compression from vertebral subluxation related to congenital abnormalities or traumaAcute disseminated encephalomyelitis (ADEM)

NEUROMUSCULAR JUNCTION DISORDERS Tick paralysis, myasthenia gravis, botulism, hypercalcemiaMyopathiesPeriodic paralyses, dermatomyositis, critical illness myopathy

OTHER NAMES

• LANDRY’S ASCENDING PARALYSIS

• ACUTE INFLAMMATORY DEMYELINATING POLYNEUROPATHY (AIDP)

• ACUTE IDIOPATHIC POLYRADICULONEURITIS

• ACUTE IDIOPATHIC POLYNEURITIS

• FRENCH POLIO

• LANDRY GUILLAIN BARRE SYNDROME

AIDP

• The most common acute neuromuscular disease seen in the intensive care unit is GBS

Epidemiology

• incidence 2 /100,000/year.

• Sex

• M/F 1.1-1.7:1

• Age

• 2 months to 95 years

• Average 15-35 years

• Childhood GBS average age is 4-8 years

Antecedent events (causes)

• 60-70% cases –post infectious .

– 1-3 weeks after an acute infectious process respiratory or GIT.

– 20-30% cases –campylobacter jejuni

– Other agents –HHV (EBV,CMV)

– Mycoplasma pneumoniae

• Recent immunisation –swine influenza vaccine,olderrabies vaccine (nervous system)

• Can be seen in patients with lymphoma,HIVpositive,SLE.

Presentation• FEVER AND CONSTITUTIONAL SYMPTOMS ARE ABSENT AT THE ONSET

AND IF PRESENT ,CAST DOUBT ON DIAGNOSIS.

• Progressive weakness usually begins in the feet. at presentation, 60% have weakness in all 4 limbs. usually symmetric.

• GBS with a descending pattern of weakness seen in 14% cases.

• Paresthesias often precede the onset of weakness by 1 or more days. Often gait ataxia with distal limb paresthesias. Pain, temp relatively spared.

• At presentation half have some facial weakness

• Ophthalmoparesis see in 10-20% of patients. (around 10%.Dyck and Thomas ). Abducens palsy most common; usually bilateral.

Oropharyngeal weakness present in almost 50% of cases

>1/3 require mechanical ventilation

Areflexia: 70% at presentation and eventually in all

58 to 76% of patients have sensory NCS abnormalities (Oh et al, NEUROLOGY 2001)

Autonomic dysfunction two thirds of patients. most common is sinus tachycardia. Retention of urine 1/3 cases, GI dysmotility 15% (Semin Neurol 2008)

plateaus 50% in 2 weeks, over 90% by 4 weeks Improvement usually begins 1-4 weeks after the plateau.

IMMUNOPATHOGENESIS

• An autoimmune basis.

• Both cellular and humoral immunity involved.

• T cells activation –IL2,IL2 receptor,IL-6,TNF alpha,IFN gamma.

• All GBS results from immune responses to non self anitgnes(infectious agents,vaccines) that misdirect to host nerve tissue through a resemblance of epitope(molecular mimicry).

• Neural targets are gangliosides.

• Anti ganglioside ab –GM1 (20-50% cases of C.jejuni)

• Anti GQ1b ab - >90% MFS

GM1 on nerve, nodes of ranvier

Anti GB1 ab as part of molecular mimicry

Complement mediated injury at

Paranodal axon – glial junction

Disrupts the cluster of sodium channels

Conduction block

Flaccid paralysis

Asbury Criteria for diagnosis

REQUIRED :• 1.progressive weakness of 2 or more limbs due to neuropathy.

• 2.areflexia

• 3.disease course < 4 weeks

• 4 exclusion of other causes (vasculitis,PAN,SLE,churg strausssyndrome,toxins,lead,botulism,diptheria,porphyria.,cauda equinalsyndrome)

SUPPORTIVE:• 1.relatively symmetric weakness

• 2.mild sensory involvement

• 3.facial nerve or other cranial nerve involvement

• 4.absence of fever

• 5.typical CSF profile(aceelualr,increase in protein level)

• 6.electrophysiologic evidence of demyelination

Variants

• MFS: most common variant, ophthalmoplegia, areflexia, and ataxia usually in adults, also common in children. Most have GQ1b Ab

• Regional variants : eg pharyngeal-cervical-brachial weakness are rare (acute progression of oropharyngeal, neck, and shoulder weakness. facial palsy, blepharoptosis, no sensory disturbance, preserved DTR in the legs, elevated CSF protein and denervation and decreased conduction velocity on EMG, reported in 1986 by Ropper )

• Pure pandysautonomia usually no weakness, many have areflexia

• AMAN China, developing countries. weakness only. little or no demyelination or inflammation, more prevalent in kids

• AMSAN

Work up

• ESR and SE are normal ,Sometimes Liver enzymes are elevated

Albuminocytologic dissociation on CSF

• protein > 55mg/dl

• cells <10 mononuclear leukocytes/ml

• 2/3 in 1st week, 82% have it by 2 weeks after symptom onset.

• no association with clinical severity.

• Some have oligoclonal bands or Myelin basic protein

• Early on, NCS often normal.

• 90% are abnormal within 3 weeks of onset.

• 3 of the 4 NCS criteria = clear primary demyelinating neuropathy (Cornblath)

• Reduced conduction velocity

• Conduction block or abnormal dispersion

• Prolonged distal latencies

• Prolonged F-waves

• Autonomic tests

• PFT: FVC < 20 mL/kg ICU; FVC< 15mL/kg or NIF<-25 Intubation

• Nerve biopsy if prolonged clinical course.

Treatment

• Initiate as soon as possible.

• Each day counts 2 weeks after the first motor symptoms –immunotherapy is no longer effective.

• IVIg IVIg-first choice,easy to administer Five daily infusions 2g/kg body weight

• Plasmapheresis - 40-50ml/kg four times a week

• Combination is not effective

• Treatment reduces need for ventilation by half.,increases full recovery at an year.

• Glucocorticoids are not effective in GBS.

• Conservative management in mild cases.

Prognosis

• total recovery in adults around 75%

• during the early stage of GBS, increasing severity in neurologic disability scores ,cranial nerve involvement, urinary incontinence, respiratory signs, and the need for ventilator support are associated with poor prognoses

• Low CMAP amplitudes (< 20% of normal) bad prognostic indicator.

• 10% may have a relapse in 1-6 weeks after completing immunomodulatory therapy

• 15% end up with significant neurological residuals

• Mortality 2-6 %

• Primary Periodic paralysis

• Secondary Periodic paralysis

Causes of Primary Periodic paralysis

– Hypokalemic (CACNA1S/ SCN4A)

– Hyperkalemic (SCN4A)

– Anderson Tawil syndrome (KCNJ2)

34

Periodic paralysis

• 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, sleep paralysis, MG, TIA, conversion

35

SecondaryPeriodic Paralysis

HYPOKALEMIC PERIODIC PARALYSIS

MUTATED GENE CALCL1A3 SCN4A

CHROMOSOME 1q31 17q

DEFECTIVE CHANNEL

CALCIUM SODIUM

MODE OF INHERITENCE

AUTOSOMAL DOMINANT

TYPE 1 TYPE 2

HYPOKALEMIC PERIODIC PARALYSISPREVELANCE 1:100,000, AD

AGE OF ONSET FIRST AND SECOND DECADE OF LIFE

M:F 3 or 4:1

SYMPTOMS DURING ATTACKS Occur anytime of the day; more common in morningAbsence of myotoniaProximal > distal weakness; legs > armsSparing of facial, ventilatoryand sphincter musclesLasts several hours to more than a day

HYPOKALEMIC PERIODIC PARALYSISSYMPTOMS BETWEEN ATTACKS REGAIN FULL STRENGTH

BETWEEN ATTACKS

TRIGGERS HIGH CARBOHYDRATE,HIGH SALT,DRUGS- BETA AGONISTS, INSULINREST FOLLOWING PROLONGED EXERCISEFEVER /LACK OF SLEEP/STRESSETOH consumption

SERUM POTASSIUM CONCENTRATION

LOW

ECG U waves, flattening of T waves

MUSCLE BIOPSY SINGLE OR MULTIPLE CENTRALLY PLACED VACUOLES

NERVE CONDUCTION TEST REDUCED AMPLITUDE OF ACTION POTENTIAL

ELECTROMYGRAPHY ELECTRICALLY SILENT

TREATMENT ORAL KCL SUPPLEMENTATIONKCL VIA INFUSIONDONOT GIVE IN DEXTROSE

PROPHYLAXIS ACETAZOLAMIDE(125-1000 Mg)

PROGNOSIS USUALLY GOODRARE DEVELOPMENT OF PROXIMAL MYOPATHY

*Never forget to measure the thyroid hormones.

Hypokalemic Periodic Paralysis

41

• Frequency Of Attacks : 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

42

PROGNOSIS

SUMMARY

• 1.acute rapidly evolving areflexic ascending motor paralysis with or without sensory disturbances.

• 2.fever is absent at the onset of weakness

• 3.bladder involvement in severe cases –transient

• 4.campylobacter jejuni 20-30 % cases

• 5.autoimmune basis ,molecular mimicry

• 6.anti GM1 ab (MC),anti GD1a,anti GQ1b (MFS)

• 7.autonomic involvement is common

• 8.facial nerve is the one most commonly affected,optic nerve.

• 9.30% require ventilatory support.

• 10.course is usually < 4 weeks

• 11 .typical CSF profile shows high protein,no pleocytosis

• 12.electrographically conduction block present

• 13.treatment as soon as possible

• 14.IVIg,plasmapheresis –both are equally good

• 15.glucocorticoids are not effective in GBS

• 16.think of miller fischer variant in presence of ophthalmoplegia,ataxia,areflexia.

HYPOKALEMIC AIDP

PREVELANCE 1:100,000 AD M>>>F 2:100,000 S M>F

AGE OF ONSET FIRST AND SECOND DECADE OF LIFE

ANY AGE SROUP[MC 2-4]

SYMPTOMS ACUTE ONSELT FLACCID PARALYSISPROXIMAL >>> DISTAL WITHOUT SENSORY COMPLAINTS BUT BODY ACHE PRESENT

ASCENDING WEAKNESS OF PROXIMAL AND DISTALMUSCLES WITH PARASTHESIAS AND PAIN

CRANIALNERVE/BULBAR/RESPIRATORY MUSCLE INVOVLMENT

RARELY SEENBLADDER/BOWEL- NOT SEENAUTONOMIC DYSFUNTION - ABSENT

COMMON++++URINARY RETENTION +CONSTIPATION +COMMONLY+++

TRIGGERS HIGH CARBOHYDRATE,HIGH SALT,FEVERDRUGS-BETAAGONISTS, INSULINREST FOLLOWING PROLONGED EXERCISE

H/O OF FEBRILE ILLNESS WITH GIT/RSINVOVLMENT PRIOR TO WEAKNESS IN 66%.H/O VACINATIONS+

HYPOKALEMIC AIDP

COURSE EpisodicLasts several hours to more than a dayAttacksFrequency : highly variableFrequency decreases after age 30; may become attack free in 40s and 50sPermanent fixed weakness or slowly progressive weakness more common with HypoKPP1

Progressive initiallyplateaus 50% in 2 weeks, over 90% by 4 weeks Improvement usually begins 1-4 weeks after the plateau3 attacks or >8 weeks -CIDP

SERUM POTASSIUM CONCENTRATION

LOW NORMAL

ECG U waves, flattening of T waves

TACHYCARDIA 2nd or 3rd degree conduction block, QRS prolongation and T wave abnormality

MUSCLE BIOPSY SINGLE OR MULTIPLE CENTRALLY PLACED VACUOLES

NI/NORMAL

NERVE CONDUCTION TEST/EMG

REDUCED AMPLITUDE OF ACTION POTENTIAL/EMG ELECTRICALLY SILENT

Primary demyelinating neuropathy

CSF EXAM NI/NORMAL Albuminocytologicdissociation on CSF