Neuromuscular Diseases

Dianna Quan

Steven P. Ringel

Disorders that result from abnormalities of spinal cord motor neurons, peripheral nerve, neuromuscular junction, or muscle constitute “neuromuscular disease.” Weakness is a common symptom, but unlike central nervous system (CNS) disorders, neuromuscular diseases may be accompanied by muscle atrophy and diminished muscle tone. Patients also may develop muscle pain, stiffness, cramps, twitching, limb deformities, or myoglobinuria.

This chapter begins with an overview of the variable clinical presentations of neuromuscular disease and a description of the tests commonly used to aid in the diagnosis of neuromuscular conditions. Subsequent sections include more detailed descriptions of specific neuromuscular disorders, excluding disorders of peripheral nerve, which will be covered in a separate chapter. For each condition, pertinent diagnostic investigations including genetic testing (Table 17.1), outpatient treatment principles (Table 17.2), special problems in managing hospitalized patients, and suggestions on when to refer to a neurologist will be discussed.

CLINICAL PRESENTATIONS

Weakness

▪ SPECIAL CLINICAL POINT: A useful clinical generalization for neuromuscular disorders is as follows:all motor neuron, neuromuscular junction, and muscle diseases have no sensory changes accompanying weakness.

Coexisting sensory loss, dysesthesias, or paresthesias strongly suggest a peripheral nerve disorder (see Chapter 18, Peripheral Neuropathy).

TABLE 17.1 Gene Abnormalities in Neuromuscular Disease

Disorder			Chromosome	Recessive (R) or Dominant (D)	Gene Product	Special Features
Motor Neuron Disease
Spinal muscular atrophy
	SMA 1,2		5	(R)	SMN and rarely NAIP protein in SMA 1,2,3	SMN protein mutation in 95% of Type 1,2,3
	SMA 3		5	(R) and (D)	SMN and rarely NAIP protein in SMA 1,2,3
	SMA 4 (adult)		Unknown	(R) and (D)	SMN defect in some	Clinical overlap with progressive muscular atrophy
Spinal and bulbar muscular atrophy (Kennedy’s disease)			X	(R)	Androgen receptor	Androgen receptor gene enlarged (multiple CAG repeats)
Amyotrophic lateral sclerosis
	Sporadic (90%-95%)		No known defect	None known	See text
	Familial (5%-10%)		No known defect
		SOD-1 mutation	21	(D)	More than 90 known mutations	SOD-1 mutation in only 20% of familial cases
		Other mutations	2,9, 15, 18	(D) or (R)	Unknown	Mutations very rare
Peripheral Nerve (See Chapter 18 )
Neuromuscular Junction
Acquired MG			No gene defect	—	—	—
Congenital MG			17	(R)	Subunit of acetylcholine receptor protein	No antibodies to the receptor protein, and immunosuppression is ineffective
Muscular Dystrophies
Duchenne/Becker dystrophy			X	(R)	Dystrophin	Gene deletion (60%-70%); point mutation in rest
Facioscapulohumeral dystrophy			4	(D)	Unknown	Specific deletions in 95% on chromosome 4, but gene itself is still unknown
Limb-girdle dystrophy (recessive)			2,4,5,13, 15, 17	(R)	2A Calpain 2B Dysferlin	LGMD2A mildly weak LGMD2B proximal and distant weakness (Myoshi)
LGMD 2A,2B,2C,2D,2E,2F,2G,2H,2E,2J					2C, D, E, F sarcoglycan defect 2G Telethonin defect 2H E-3 Ubiquitin defect 21 Fukutin-related protein 2J Titan-related protein	LGMD 2C-J tend to have severe symptoms, some resembling Duchenne dystrophy (see text)
Limb-girdle dystrophy (dominant)
	LGMD1A		5	(D)	Myotilin	Dysarthria seen
	LGMD1B		3	(D)	Caveolin	“Rippling” muscle
	LGMD1C		1	(D)	Laminin	Cardiac involvement
Emery-Dreifuss muscular dystrophy			X	(R)	Emerin	Elbow contractures and cardiac changes
Congenital muscular dystrophy			1,6	(R)	Absent merosin in some	Normal mentation
Congenital muscular dystrophy			9	(R)	Fukutin defect	Severe mental and developmental retardation
Oculopharyngeal dystrophy			14	(D)	Protein regulates polyadeny-lation and mRNA size	Ptosis, swallowing defects
Myotonias
Myotonia congenita			7	(D) and (R)	Muscle chloride channel	Autosomal recessive form most common; dominant forms rare (Thomsen’s disease)
Myotonic dystrophy (DM1)			19	(D)	Myotonin	Gene has triplet (CCTG) repeats Disease worse with increasing number of repeats
Myotonic dystrophy (DM2 or PROMM)			3	(D)	An mRNA binding protein	Gene has multiple CCTG repeats
Inflammatory Myopathies
Inclusion body myositis			9	(R)	Unknown	Rare autosomal dominant form (most IBM is sporadic)
Glycogen Storage Diseases
Phosphorylase deficiency (McArdle’s)			11	(R) and (D)	Muscle phosphorylase	Exercise intolerance, cramps
Acid maltase deficiency			17	(R)	Acid maltase	Fatal in infants; moderately severe in adults
PFK deficiency			1	(R)	Phosphofructokinase	Exercise intolerance
PGAM-M deficiency			7	(R)	Phosphoglycerate mutase	Exercise intolerance
PGK deficiency			X	(R)	Phosphoglycerate kinase	Myopathy rare
LDH deficiency			11	(R)	Lactic dehydrogenase	Myopathy rare
Debranching enzyme deficiency			21	(R)	Debranching enzyme	Survival to adulthood common
Branching enzyme deficiency			3	(R)	Branching enzyme	Early death common
Phosphorylase b kinase deficiency			X, 16,7,6	(R)	Phosphorylase b kinase	Fatal in infancy, moderately severe in adults
Lipid Storage Disorders
CPT II deficiency			1	(R)	Carnitine palmitoyl transferase 11	Diagnosis by muscle biopsy and CPT enzyme assay
Carnitine deficiency			Unknown	(R)	Unknown	Diagnosis by muscle biopsy and muscle carnitine assay
Mitochondrial Myopathies
Kearns-Sayres syndrome (KSS)			Mitochondrial DNA	Maternal inheritance	Various mitochondrial proteins	Extraocular muscle paresis, cardiac conduction block
MELAS			“	“	tRNA	Lactic acidosis, stroke
MERRF			“	“	tRNA	Myoclonus epilepsy, ataxia Diagnosis by distinctive muscle biopsy changes
Congenital Myopathies
Myotubular myopathy
	Neonatal, late infantile, adult-onset forms		X in some	(R) and (D)	Myotubularin in neonatal form	Neonatal often fatal
	Neonatal, late infantile, adult-onset forms		Unknown	(R) and (D)	Unknown in adult form
Central core disease			19	(D)	Ryanodine receptor	Same gene as for malignant hyperthermia
Nemaline myopathy			1,2,19	(R) and (D)	Mutations reported in nebulin, alpha actin, alpha and beta tropomyosin, troponin	Respiratory problems common
Channelopathies
Hypokalemic periodic paralysis			1	(D)	Muscle calcium channel	Diaphragm never involved
Hyperkalemic periodic paralysis/paramyotonia congenital/potassium aggravated myotonia			17	(D)	Muscle sodium channel	Different mutations of sodium channel gene define unique clinical features of each
SMA, spinal muscular atrophy; SMN, survival motor neuron; NAIR neuronal apoptotic inhibitory protein; CAG, cytosine-adenine-guanine; SOD, superoxide dismutase; MG, myasthenia gravis; LGMD, limb-girdle muscular dystrophy; mRNA, messenger ribonucleic acid; CTG, cytosine-thymine-guanine; DM, myotonic dystrophy; PROMM, proximal myotonic myopathy; PFK, phosphofructo kinase; PGAM-M, phosphoglycerate mutase; PGK, phosphoglycerate kinase; LDH, lactic dehydrogenase; CPT, carnitine palmitoyl transferase; MELAS, mitochondrial myopathy, encephalopathy, lactacidosis. stroke; tRNA, transfer RNA; MERFF, myoclonus epilepsy with ragged-red fibers.

TABLE 17.2 Pharmacologic Treatments

Disorder	Drug Start Dose; Expected Effect		Stable Dose Range	Interactions/Side Effects
Motor Neuron Disease
Amyotrophic Lateral Sclerosis Sporadic or familial
Amyotrophic Lateral Sclerosis Sporadic or familial	RILUZOLE 50 mg bid		50 mg bid	Abnormal hepatic enzymes in 5%—stop drug
		Extends life 2-3 months		Abnormal hepatic enzymes in 5%—stop drug
	ANTIOXIDANTS (theoretic value—no trials)
		Vitamin E 800 lU/day Vitamin C 1000 mg/day Coenzyme Q10-50 mg/day	800 IU/day 1000-3000 mg/day None 50-300 mg/day	None None None
	PSEUDOBULBAR AFFECT
		Nortriptyline 10 mg bid Dextromethorphan 25 mg and quinidine 25 mg	Up to 50 mg tid as tolerated Recent trial using this dose (unpublished)	Excessive sleepiness Nausea, dizziness, sleepiness, loose stools
	CRAMPS
		Baclofen 10-20 mg bid Quinine 325 mg/day	20-40 mg qid	Muscle weakness at higher doses Ringing in ears
	EXCESS SALIVA		325 mg bid to tid	Sleepiness
		Nortriptyline 10 mg bid
Neuromuscular Junction
Myasthenia gravis	Prednisone 50 mg/day		50-80 mg/day depending on patient weight. Try tapering dose after strength back to normal. Use with azathioprine.	Weight gain, mood changes, cataract, osteopenia, diabetes, hypertension
	Azathioprine 50 mg/day		Increase each week by 50 mg increments until taking 50 mg qid.Add on to stable prednisone dose and after 2-3 months, try tapering the prednisone.	May cause leukopenia and liver function abnormalities, so monitor with weekly studies until maximal dose reached. Then, can do blood safety studies every 3 months. Also may cause skin rash.
	mycophenolate mofetil 0.5 g/day		Increase over 2-3 weeks to I g bid	Not authorized by FDA for MG. Used primarily as antirejection drug for organ transplant but occasionally of use in MG when other drugs fail. Major side effect is Gl distress.
	Pyridostigmine 60 mg q4hr		60-120 mg q4hr, 180 mg timespan appropriately spaced	Symptomatic only and used primarily for mild ocular symptoms when risk of immunosuppression is unacceptable. Overdosage and cholinergic crisis can occur, however.
	Plasma exchange IVIG 400 mg/kg		3-5 daily exchanges and repeat as needed	Used for acute worsening if best pharmacologic treatment fails.
			400 mg/kg × 5 days, reassess; repeat as needed	Used in patients totally refractory to all other therapy.
Muscular Dystrophies
Duchenne and Becker	Prednisone 0.65 mg/kg		Maintain at this dose for months to years depending on side effects	Treatment is controversial, and there are steroid side effects, as described for MG. In addition, there is growth retardation in children.
Myotonias
Myotonia congenita	Mexilitine 150 mg bid		Increase by 50 mg increments every week to a maximum of 200 mg tid	Gl distress, lightheadedness, tremor are side effects. Drug interactions with phenytoin, phenobarbital, rifampin, cimetidine, and theophylline.
Lipid Storage Disorders
Carnitine deficiency	L-carnitine 2—4 g/day in adults 100 mg/kg/day (children)		Maintain at starting doses
Channelopathies
Hypokalemic periodic paralysis	Acetazolamide 250 mg bid		Increase to 250 mg tid as needed	Interactions with various drugs. Taste change, anorexia, nausea, drowsiness, kidney stones.
Hyperkalemic periodic paralysis	Hydrochlorthiazide 25 mg/day in AM		Increase to 50 mg/day in AM, and add 12.5 mg in PM, if necessary	Interactions with various drugs. Weakness, hypotension, electrolyte disturbance.
FDA, Food and Drug Administration; MG, myasthenia gravis; Gl, gastrointestinal; 1VIG, intravenous immune globulin.

The rapidity of onset, location, and progression of weakness are important diagnostic features. Rapidly developing weakness (hours to several days) is characteristic of diseases of the neuromuscular junction, Guillain-Barré syndrome, toxic myopathies, and acute electrolyte disturbances. Acute remissions and relapses may be seen with myasthenia gravis (MG), periodic paralysis, and other channelopathies. Insidious and slowly progressive weakness occurs in many diseases affecting muscle or spinal cord motor neurons. Three major patterns of weakness can be encountered: proximal, distal, or cranial. Each pattern is associated with typical symptoms related by the patient and with some signs easily observed even before individual muscles are tested.

Proximal weakness is characteristic of many muscle disorders, the spinal muscular atrophies, and MG. These patients report difficulty in climbing stairs or arising from low chairs. When arising from a chair, they will lean forward and “push off” with their hands on the armrests. In arising from the floor or a squatting position, they may require one or more supports with the hands on the floor, knees, and thighs (Gowers maneuver; Fig. 17.1). The gait of a person with proximal weakness has a waddling appearance because of hip girdle weakness. Knee extensor weakness may cause the leg to “give out.” Patients may lock their knees to compensate, gradually leading to hyperextension (back-kneeing), which in turn produces an exaggeration of the lumbar lordosis. Shoulder girdle weakness produces difficulty in elevating the arms and may be accompanied by scapular winging (Fig. 17.2). With the arms hanging at the sides, the scapulae may slide laterally to produce a curving inward of the shoulders with the backs of the hands facing forward and an associated oblique “axillary crease” (Fig. 17.3). The high-riding scapulae produce a conspicuous “trapezius hump”; the clavicles may slope downward and stand out prominently from the atrophic neck musculature (Fig. 17.3).

FIGURE 17.1 Gowers maneuver displayed in arising from the floor (Duchenne muscular dystrophy).

FIGURE 17.1 Continued

FIGURE 17.2 Winging of the scapulae when the arms are elevated (fascioscapulohumeral dystrophy [FSH]).

FIGURE 17.3 Shoulder girdle weakness with “trapezius hump,” “step-sign” with prominent downsloping clavicles, and an oblique anterior axillary crease (LGD).

Distal weakness in the presence of atrophy is commonly seen in amyotrophic lateral sclerosis (ALS) (Fig. 17.4), inclusion body myositis (IBM), and myotonic dystrophy. Patients with ALS or IBM may present with unilateral symptoms but eventually develop weakness bilaterally. These patients find it difficult to manipulate small objects such as buttons or writing or eating utensils. They may complain of “dragging” their legs because of “foot drop” or of frequent tripping, particularly on uneven ground. With each step, the knees are raised high while the feet flap limply; shoe soles may show asymmetrical wear.

Cranial weakness may manifest as extraocular, facial, or oropharyngeal muscle weakness and is an important differential feature in diagnosis of various dystrophies (Figs. 17.5 and 17.6). Ptosis and ophthalmoparesis occur in several myopathic disorders and are very common in MG. Swallowing and speech changes can also be early signs of either ALS or MG.

FIGURE 17.4 Marked atrophy of the first dorsal interosseous muscle in motor neuron disease.

FIGURE 17.5 Typical facial appearance in myotonic dystrophy with frontal balding, temporalis and masseter atrophy, ptosis, and protuberant lower lip.

FIGURE 17.6 Myotonic dystrophy in mother (note “hatchet face”) and infant (note “shark mouth”). Diagnosis first made in the child suggested the same diagnosis in the mother.

Atrophy and Hypertrophy

The disuse of a limb will produce modest muscle atrophy, as is seen in nonneuromuscular conditions such as after casting of a bone fracture. The muscle retains much of its strength in disuse atrophy, and the apparently atrophied limbs of an elderly person may be surprisingly strong. In contrast, the striking muscular atrophy in patients with neuromuscular disease is associated with obvious weakness.

Atrophy of the muscles around the shoulder girdle commonly reveals underlying bony prominences. Flattening of the thenar eminence and guttering of the interossei can produce a wasted, clawlike deformity of the hand (Fig. 17.4). Several disorders produce characteristic appearances. Examples include “Popeye arms” (very atrophied biceps/triceps with a normal-appearing forearm) in facioscapulohumeral dystrophy, the “hatchet face” (temporalis wasting) appearance in myotonic dystrophy (Figs. 17.5 and 17.6), and
the enlarged calves of Duchenne dystrophy (DUD; Fig. 17.7). Diffuse hypertrophy of all limb muscles is commonly seen in myotonia congenita, rarely in hypothyroidism, or very rarely in amyloidosis.

FIGURE 17.7 Pseudohypertrophy of the calves (Duchenne dystrophy).

Pain, Stiffness, and Cramps

Pain is a nonspecific symptom that may be seen in many neuromuscular conditions. Inflammatory myopathies and other collagen vascular diseases may produce muscle pain and tenderness, but the absence of these symptoms does not exclude the diagnosis. Some patients may have difficulty distinguishing between pain and weakness because pain limits their ability to perform motor tasks. This may result in perceived weakness. Such individuals often prove to have normal strength or a “give-away” pattern of weakness, which suggests lack of full voluntary effort.

▪ SPECIAL CLINICAL POINT: Most patients with limb aching and pain without objective weakness or abnormally elevated muscle enzymes do not have a neuromuscular disease, and other possibilities should be considered, such as joint or soft tissue pathology.

In older patients, pain, aching, and stiffness in the shoulder and hip girdle muscles should suggest polymyalgia rheumatica, and this disorder is associated with a very high sedimentation rate. It is important to recognize because of its very specific treatment and rapid response to steroid medications. The diagnosis of fibromyalgia often is evoked, particularly in otherwise healthy individuals who have diffuse aches and pains without objective signs of weakness; however, the pathologic foundation of this entity remains controversial.

Stiffness may be a nonspecific symptom, or it may be a symptom of myotonia, a phenomenon consisting of a delayed relaxation of the muscle following voluntary contraction or percussion. This produces difficulty in releasing the grip or initiating movements after a period of rest and may point to a myotonic dystrophy or myotonia congenita.

Muscle cramp, a prolonged involuntary contraction, is a universal and generally benign symptom that occurs with increased frequency during unaccustomed exercise, “body building,” pregnancy, or electrolyte disturbance. It also may occur in hypothyroidism, partial denervation due to ALS or other less sinister types of nerve injuries, tetany (with hypocalcemia, hypomagnesemia, or alkalosis), and certain metabolic myopathies.

Muscle Twitching

Fasciculations are contractions of muscle fibers in a single motor unit. Fasciculations appearing in a strong muscle are usually benign and are exacerbated by many factors, including fatigue and caffeine intake. When they occur in a weak muscle, they may be associated with ALS, but they also may occur in the setting of root compression or peripheral nerve injury.

Infantile Hypotonia

The most frequent abnormality causing infantile hypotonia or a “floppy baby” is CNS disease, such as seen after perinatal asphyxia. The hypotonic infant may exhibit normal muscle strength, with the ability to lift its head or limbs against gravity. In the absence of other abnormalities, the prognosis for normal development may be excellent. In infants with obvious weakness, the underlying disorder may be spinal muscle atrophy or one of the congenital myopathies. Weakness of sucking and respiration are serious concomitant findings, which are usually fatal if undiagnosed and untreated.

Deformities

Neuromuscular disorders often are associated with skeletal deformities and should be suspected in a patient with unexplained hip dislocation, scoliosis (Fig. 17.8), contracture, or malformation of the feet (e.g., clubfoot, equinovarus, or pes cavus deformity). Arthrogryposis or multiple congenital limb deformities may occur with various diseases affecting any part of the motor unit.

FIGURE 17.8 Scoliosis in chronic infantile spinal muscular atrophy. The angle of curvature is measured and followed closely (55 degrees in this patient).

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