Introduction
Channelopathies are a group of diseases with abnormal channels resulting from genetic disor-ders. Channels are pores in cell membranes that allow ions to enter or exit a cell to depolarize or
CHAPTER 4—Disorders of Muscle 45
Figure 4-4 Muscle biopsy of dermatomyositis. (Courtesy of Alan Pestronk, MD.) 039-048_Davis04 3/2/05 4:10 PM Page 45
hyperpolarize the cell. These macromolecular pro-tein complexes with the lipid membrane are divided into distinct protein units called subunits.
Each subunit has a specific function and is encoded by a different gene. A channel may be non-gated, directly gated, or second-messenger–
gated. Important directly gated channels include voltage-gated channels (sodium, potassium, cal-cium, and chloride) and ligand-gated channels (acetylcholine, glutamate, γ-aminobutyric acid (GABA), and glycine).
Genetic mutations in critical areas of a channel can produce an abnormal gain of function (addi-tional properties not present in the normal pro-tein) or loss of function (loss of properties present in the normal protein). Channelopathy diseases primarily affect excitable cells such as muscle fibers and neurons and produce signs and symptoms that are often episodic.
Primary hyperkalemic periodic paralysis (hyper-kalemic PP) belongs to a group of channelopathies with mutations in the voltage-gated sodium chan-nel. Other sodium channelopathies include famil-ial generalized epilepsy with febrile seizures, paramyotonia congenital, and hypokalemic peri-odic paralysis.
Pathophysiology
Hyperkalemic PP is due to a dominant mutation in chromosome 17q35 that affects the α-subunit (SCN4A) of the sodium channel (Figure 4-5). Of all cases, 90% are the result of two mutations, one of which produces both periodic flaccid weakness and myotonia.
The muscle membrane in a patient with hyper-kalemic PP contains 2 types of sodium channels. A normal channel from the normal gene activates (opens) and then inactivates (closes) rapidly.
However, the mutated sodium channel activates appropriately but inactivates abnormally slow.
In normal muscle, hyperkalemia causes a few normal sodium channels to open. The subsequent slight membrane depolarization is rapidly cor-rected as the channels close before the depolariza-tion is sufficient to cause muscle contracdepolariza-tion.
However, in hyperkalemic PP muscle, the hyper-kalemia opens both the normal sodium channel and the mutated sodium channel. The mutated sodium channel remains open for a prolonged period, allowing excess entry of sodium into the
muscle cell. The excess intracellular sodium in turn produces a prolonged depolarization. The net result is that the depolarized muscle fiber becomes paralyzed, electrically unexcitable, and nonrespon-sive to future nerve stimulation.
The sodium influx allows efflux of intracellular potassium into the extracellular space and also causes extracellular water to enter the muscle fiber, resulting in hemoconcentration. Both result in a further rise in serum potassium level. The elevated potassium level triggers more muscle fibers to become persistently depolarized and the entire muscle rapidly becomes paralyzed. The cycle ends when the serum potassium level returns to normal by the kidney’s excretion of potassium and likely by other corrective measures. The duration of paralysis may be 15 minutes to hours.
Normal individuals can develop muscle paraly-sis if their serum potassium level rises above 7 mmol/L. Hyperkalemia may occur in renal failure, adrenal insufficiency, and exposure to the diuretic spironolactone.
Major Clinical Features
The paralysis attacks usually begin in the first decade of life and are infrequent. With increasing age the attacks become more frequent. In severe cases, they occur daily. Most episodes occur in the morning before breakfast. Attacks during the day are often precipitated by strenuous exercise fol-lowed by rest. Other triggers include consumption of excess potassium, emotional stress, fasting, a cold environment, and corticosteroid administration.
At the start of an attack the patient may experi-ence paresthesias or sensations of increased muscle tension. The patient then develops a flaccid gener-alized weakness and cannot move the arms, legs, and trunk. The weakness spares respiration mus-cles, cranial nerves, and bladder and bowel sphinc-ters. The attack lasts 15 minutes to 1 hour before spontaneously disappearing. Afterwards, strength returns to normal and the individual commences normal activity. Over years, patients with severe hyperkalemic PP may develop permanent muscle weakness.
One mutation causes varying amounts of myotonia between attacks. The clinical symptom of myotonia is essentially a slowing of relaxation of a normal muscle contraction and is commonly inter-preted by the patient as “stiffness.” Commonly the 46 FUNDAMENTALS OF NEUROLOGIC DISEASE
039-048_Davis04 3/2/05 4:10 PM Page 46
patient cannot easily release a grip on an object. A cold environment often makes myotonia worse.
Major Laboratory Findings
During an attack, the serum potassium level rises up to 5 to 6 mmol/L but rarely reaches cardiotoxic levels. The serum sodium level falls slightly as the ion enters muscle fibers. Renal excretion of potas-sium occurs, with elevated urine potaspotas-sium levels.
The serum CK level is normal to slightly elevated during an attack.
Between attacks, the serum potassium level is usually in the upper normal range and the urinary potassium level is normal.
During an attack, EMG studies of paralyzed muscle show electrical silence. Between attacks, the EMG finding in the most common mutation is normal, while myotonia is seen in the less-com-mon mutation. In myotonia, insertion of the EMG needle into a muscle causes a train of rapid electri-cal discharges that have a falling amplitude and frequency and sound like a “dive-bomber” when heard on the EMG speaker. Myotonia is due to
CHAPTER 4—Disorders of Muscle 47
Normal
B. Depolarizing Phase A. Resting
State
D. Hyperpolarization C. Repolarizing
Phase
Hyperkalemic Periodic Paralysis
B2 Delay in Inactivation
Gate A
B C
D
Activation Gate
Inactivation Gate Na+
Channel
K+
Channel
A B
C
D B2
Na+
Na+ K+
K+
K+
K+
Na+
Na+
K+
K+
Figure 4-5 Hyperkalemic periodic paralysis is due to a dominant mutation in chromosome 17q35 that affects the α-subunit (SCN4A) of the sodium channel.
039-048_Davis04 3/2/05 4:10 PM Page 47
increased excitability of muscle fibers from the channelopathy (sodium channels or potassium channels in other myotonic diseases), producing repetitive action potentials in individual muscle fibers.
Muscle histology may be normal or demon-strate nonspecific changes to muscle fibers. In patients who develop permanent myopathy, mus-cle fibers may show vacuolations in musmus-cle fibers, focal myofibrillar degeneration, and central nuclei.
Since the gene for hyperkalemic PP is known, blood tests are available for detection of the most common mutations. However, the diagnosis is commonly made in a patient with periodic paraly-sis who has a dominant family history and tran-sient elevation of serum potassium level during an attack.
Principles of Management and Prognosis Since most attacks are brief, many patients do not require any drug treatment. Some patients can abort or shorten an attack by consuming carbohy-drates or performing mild exercise at the start of an attack. Patients with severe frequent attacks
may benefit from chronic administration of thi-azide or acetazolamide diuretics, which lowers the serum potassium level.
RECOMMENDED READING
Davies NP, Hanna MG. The skeletal muscle chan-nelopathies: basic science, clinical genetics and treatment. Curr Opin Neurol 2001;24:539–551.
(Recent review of all channelopathies that affect muscle.)
Emery AEH. The muscular dystrophies. Lancet 2002;359:687–695. (Nice review of current status of all muscular dystrophies.)
Hilton-Jones D. Inflammatory muscle disease.
Curr Opin Neurol 2001;14:591–596. (Reviews dermatomyositis, polymyositis, and inclusion body myositis.)
Pestronk, Alan. www.neuro.wustl.edu/neuromus-cular (Outstanding, accurate, current online information on clinical, laboratory, pathology, and treatment of all muscle and peripheral nerve diseases.)
48 FUNDAMENTALS OF NEUROLOGIC DISEASE 039-048_Davis04 3/2/05 4:10 PM Page 48
Overview
In humans, all nerve-to-nerve, nerve-to-muscle, and peripheral sensory receptor-to-nerve commu-nication occurs via synapses. An electrical signal traveling along a nerve axon is converted at a spe-cialized nerve ending called a synapse. At the synapse the electrical signal triggers release of a neurotransmitter into the synaptic cleft. The neu-rotransmitter then crosses the synaptic cleft to attach to a specialized receptor that is part of an ionic channel, resulting in either local depolariza-tion or hyperpolarizadepolariza-tion of the postsynaptic cell.
When sufficient ionic channels have been stimu-lated by neurotransmitters, the postsynaptic cell either completely depolarizes or becomes inhib-ited from depolarizing. In summary, all neural communication results from electrical-to-chemi-cal-to-electrical transmission.
There are at least 30 different types of neuro-transmitters, with the greatest number occurring in the CNS. In simple terms, neurotransmitters are classified into simple chemicals (acetylcholine, norepinephrine, and dopamine), amino acids (GABA, glycine, and glutamine), or peptides (sub-stance P and endorphins). The duration of the neurotransmitter effect may be milliseconds, as in a brief opening and closing of an ionic channel, to
hours or days, as when a receptor stimulates intra-cellular second messengers that enzymatically affect intracellular pathways.
Synaptic disorders may occur from chemical or biologic toxins, antibodies directed against synaptic receptor molecules, or genetic mutations in the synaptic receptor or membrane channel. Synaptic disorders due to mutations in calcium, potassium, and sodium ion channels (called channelopathies) are responsible for such episodic disorders as seizures, migraine-type headaches, ataxia, myoto-nia, and weakness from Lambert–Eaton syndrome.
Synaptic disorders often have several suggestive clinical features: (1) excessive inhibition or excita-tion of one transmitter pathway, (2) signs and symptoms that are episodic or fluctuate consider-ably, and (3) signs that increase with continuing firing of the synapse.
This chapter focuses on diseases that result from toxins and antibodies affecting the neuro-muscular junction to produce weakness.