Periodic Paralyses Clinical Presentation
- Author: Naganand Sripathi, MD; Chief Editor: Nicholas Lorenzo, MD more...
History
All periodic paralyses (PPs) are characterized by episodic weakness. Strength is normal between attacks. Fixed weakness may develop later in some forms. Most patients with primary PP develop symptoms before the third decade.
- Hyperkalemic periodic paralyses
- Age at onset is younger than 10 years. Patients usually describe a sense of heaviness or stiffness in the muscles. Weakness starts in the thighs and calves, which then spreads to arms and neck. Proximal weakness predominates; distal muscles may become involved after vigorous exercise.
- In children, a myotonic lid lag (lagging of upper eyelid on downward gaze) may be the earliest symptom. Complete paralysis is rare and some residual mobility remains. Respiratory muscle involvement is rare. The attacks last less than 4 hours and in the majority of cases, less than 1 hour. Sphincters are not involved; any bowel and bladder dysfunction is due to abdominal muscle weakness.
- Weakness occurs during rest after a period of strenuous exercise or during fasting. It also may be provoked by potassium, cold, ethanol, or stress. It may be relieved by mild prolonged exercise or carbohydrate intake. Patients also may report muscle pains and paresthesias. Between attacks, clinical and electrical myotonia is present in the majority of patients. Some families have no myotonia. Clinically apparent myotonia is seen less than 20% of patients, but electrical myotonia may be found in 50-75%. Interictal weakness, if present, is not as severe as in hypokalemic PP.
- Hypokalemic periodic paralyses
- This can be divided into HypoPP1 (calcium channel mutation) and HypoPP2 (sodium channel mutation).
- Severe cases present in early childhood and mild cases may present as late as the third decade. A majority of cases present before age 16 years. Weakness may range from slight transient weakness of an isolated muscle group to severe generalized weakness. Severe attacks begin in the morning, often with strenuous exercise or a high carbohydrate meal on the preceding day. Sometimes, the time between premonitory symptoms to full-blown attack is in order of minutes. Attacks may also be provoked by stress, including infections, menstruation, lack of sleep, and certain medications (eg, beta-agonists, insulin, corticosteroids). Patients wake up with severe symmetrical weakness, often with truncal involvement.
- Mild attacks are frequent and involve only a particular group of muscles, and may be unilateral, partial, or monomelic. This may affect predominantly legs; sometimes, extensor muscles are affected more than flexors. Duration varies from a few hours to almost 8 days but seldom exceeds 72 hours. The attacks are intermittent and infrequent in the beginning but may increase in frequency until attacks occur almost daily. The frequency starts diminishing by age 30 years; it rarely occurs after age 50 years.
- Urinary output is decreased during the attack because water accumulates intracellularly in muscles. In HypoPP1 patients, the age of onset is earlier (10 y), the symptoms lasts longer (20 h), and the fixed proximal weakness is more frequent (about 70%), compared with HypoPP2 patients (16 y, 1 h, none).
- Permanent muscle weakness may be seen later in the course of the disease and may become severe. Hypertrophy of the calves has been observed. Proximal muscle wasting, rather than hypertrophy, may be seen in patients with permanent weakness.
- HypoPP2 differs from HypoPP1 by (1) late onset, (2) tubular aggregates in muscle biopsy (vacuolar myopathy in HypoPP1), (3) aggravation by acetazolamide in HypoPP2.
- Paramyotonia congenita
- In this autosomal dominant inherited disorder, myotonia worsens with activity (paradoxical myotonia) or cold temperatures.
- Symptoms are most pronounced in the face, tongue, and hand muscles with lesser involvement of lower limb.
- Muscle hypertrophy may be seen in 30% of patients.
- Myotonia lasts for seconds to minutes, but weakness may persist for hours and sometimes days. Frequency of paralytic attacks declines with age.
- Permanent and severe myopathy is more frequent in patients with periodic paralysis.
- Episodic weakness also may develop after exercise or cold temperatures and usually lasts only a few minutes, but may last as long as days.
- Potassium loading usually worsens the symptoms, but in some cases, lowering the serum potassium level precipitates the attacks.
- Thyrotoxic periodic paralyses
- Thyrotoxicosis periodic paralyses (TPP) are the most common secondary hypokalemic PP. TPP is most common in adults aged 20-40 years. Hyperinsulinemia, a carbohydrate load, and exercise are important in precipitating paralytic attacks. Weakness is proximal and, if severe, may involve respiratory or bulbar muscles. Attacks last hours to days.
- The prevalence of TPP in patients with thyrotoxicosis is estimated to be 0.1-0.2% in Caucasians and 13-14% in Chinese. Ninety-five percent of TPP cases are sporadic. As TPP is more common in Asians, a genetic predisposition is strongly suspected. Familial clustering of TPP indicates unmasking of an inherited disease (which is sporadic) by thyrotoxicosis. A mutation in KCNE3 potassium channel gene was identified in one series.[6]
- Andersen-Tawil syndrome
- Andersen-Tawil syndrome is characterized by variable expression of the 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 hours to several days may arise spontaneously but usually follows physical activity. The periodic paralysis is not associated with myotonia.
- Prolonged QT interval and ventricular arrhythmias are the most common cardiac manifestations. Other ECG abnormalities include PVCs, ventricular bigeminy, supraventricular and ventricular tachycardias, prominent U waves, and torsades de pointes. Bidirectional ventricular tachycardia, which is characterized by beat-to-beat alternating QRS axis polarity, is unique to a subset of patients. Patients may be completely asymptomatic. Patients may experience palpitations, syncopal episodes, and cardiac arrest. Sudden cardiac death is less frequent in ATS when compared with the other long QT syndromes.
- Andersen-Tawil syndrome should always be considered in any patient with periodic paralysis as facial dysmorphism may be subtle and cardiac symptoms are not always present in spite of an abnormal ECG.
Physical
Most of the patients with a periodic paralysis (PP) have similar clinical features, which are as follows:
- Interictal lid lag and eyelid myotonia - May be the only clinical signs in hyperkalemic PP
- Normal sensation
- Fixed proximal weakness - May develop in patients with either hyperkalemic or hypokalemic PP
- Diminished stretch reflexes during attacks
Table 2. Distinguishing Features Among the Common Forms of Periodic Paralyses (Open Table in a new window)
| Syndrome | Age of Onset | Duration of Attack | Precipitating Factors | Severity of Attacks | Associated Features |
| 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 | Variable -Childhood to third decade Majority of cases before 16 years | Few hours to almost a week Typically no longer than 72 h | Early morning attacks after previous day physical activity High-carbohydrate meal, Chinese food, alcohol Cold, change in barometric pressure or humidity Fever, upper respiratory tract infections 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 |
| 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 h | Cold | Rarely severe | Pseudo-hypertrophy of muscles Paradoxical myotonia Fixed weakness rare |
| Thyrotoxic periodic paralyses | Third and fourth decades | Few hours to 7 d | Same as hypokalemic PP Hyper-insulinemia | Same as hypokalemic PP | Fixed muscle weakness may develop Hypokalemia during attacks |
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- Table 1. Primary Periodic Paralysis
- Table 2. Distinguishing Features Among the Common Forms of Periodic Paralyses
- Table 3. Differential Diagnosis of Secondary Periodic Paralyses
- Table 4. Differential Diagnosis of Other Entities Causing Acute Generalized Weakness
- Table 5. Medical Conditions Associated With Hypokalemia
- Table 6. Diagnostic Studies of Hypokalemic and Hyperkalemic Periodic Paralyses
- Table 7. Electrophysiological Patterns to Exercise Testing
| Sodium channel | Hyperkalemic PP (HyperPP) Hypokalemic PP (HypoPP2) Paramyotonia congenita |
| Calcium channel | Hypokalemic PP (HypoPP1) |
| Potassium channel | Andersen-Tawil syndrome Hyperkalemic PP or hypokalemic PP* |
| *The deficit was described in 2 small families and has not been substantiated by others.[1, 2] | |
| Syndrome | Age of Onset | Duration of Attack | Precipitating Factors | Severity of Attacks | Associated Features |
| 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 | Variable -Childhood to third decade Majority of cases before 16 years | Few hours to almost a week Typically no longer than 72 h | Early morning attacks after previous day physical activity High-carbohydrate meal, Chinese food, alcohol Cold, change in barometric pressure or humidity Fever, upper respiratory tract infections 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 |
| 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 h | Cold | Rarely severe | Pseudo-hypertrophy of muscles Paradoxical myotonia Fixed weakness rare |
| Thyrotoxic periodic paralyses | Third and fourth decades | Few hours to 7 d | Same as hypokalemic PP Hyper-insulinemia | Same as hypokalemic PP | Fixed muscle weakness may develop Hypokalemia during attacks |
| Hypokalemic | Hyperkalemic |
Urinary potassium-wasting syndromes
| |
| Alcohol | Addison disease Chronic renal failure Hyporeninemic Hypoaldosteronism |
| Drugs - Amphotericin B, barium | Ileostomy with tight stoma |
| Renal tubular acidosis | Potassium load |
GI potassium-wasting syndromes
| Potassium-sparing diuretics |
| Disorder | Pattern and Distribution of Weakness |
| Transient ischemic attacks | Follow CNS distribution (ie, hemiparetic) May have sensory symptoms and signs |
| Sleep attacks | Occur at onset or termination of sleep Last only minutes |
Myelopathy
| Sensory symptoms Presence of a sensory level Sphincter involvement |
| Myasthenia gravis Lambert-Eaton myasthenic syndrome | Subacute in onset Associated autonomic symptoms in LEMS Hyporeflexia in LEMS Abnormal repetitive nerve stimulation Presence of distinct antibodies |
Peripheral neuropathy of acute onset
| Pattern of weakness Absent stretch reflexes |
Toxins
| Clinical presentation |
| Urine K/C Ratio | Acid Base Status | Other Associated Features | Medical Conditions |
| < 1.5 | Metabolic acidosis | Lower GI loss – Laxative abuse, diarrhea | |
| < 1.5 | Metabolic alkalosis | Normal BP | Surreptitious vomiting |
| >1.5 | Metabolic acidosis | DKA, type 1 or type 2 distal RTA | |
| >1.5 | Metabolic alkalosis | Normal BP | Diuretic use, Bartter syndrome, Gitelman syndrome |
| ≥1.5 | Metabolic alkalosis | Hypertension | Primary aldosteronism, Cushing syndrome, renal artery stenosis, congenital adrenal hyperplasia, apparent mineralocorticoid excess, Liddle syndrome |
| Hypokalemic PP | Hyperkalemic PP | |
| Serum potassium | Mildly depressed; may reach 1-5 mEq/L | Increases from baseline but may not increase beyond normal range |
| Serum CPK | Moderately elevated during attacks | Mildly elevated during attacks |
| ECG | Bradycardia Flat T waves, U waves, ST-segment depression | Tall T waves |
| Para- myotonia Congenita | Hyper- kalemic Periodic Paralysis | Hypo- kalemic Periodic Paralysis | |
| Electrophysiological pattern | I | IV | V |
| Channel mutations | Sodium T1313M, R1448C | Sodium T704M | Calcium R528H |
| Short Exercise Test: | |||
| Post exercise myotonic potentials | Yes | No | No |
| CMAP amplitude change after First trial | Increase or decrease | Increase | No |
| CMAP amplitude change after second and third trial | Gradual increase | Gradual increase | No |
| Long Exercise Test: | |||
| Immediate change of CMAP amplitude | Decrease | Increase | No |
| Late change of CMAP amplitude | Decrease | Decrease | Decrease |
| Modified from Fournier et al, 2004.[9] | |||
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