Skeletal Muscle and Peripheral Nerve Disorders

Clinical Features

Although denervation atrophy is not a disease unto itself, it is among the most common diagnoses found in muscle biopsy specimens. Elderly patients with radiculopathies and/or neuropathies often have clinical and laboratory features suggestive of muscle disease: weakness that is not obviously distal, elevated creatine kinase, and unreliable physical findings.

Prognosis and Therapy

The prognosis and treatment depend on the specific disease responsible for the loss of muscle innervation. (Many of these diseases are discussed in the second part of this chapter.)

Clinical Features

Myasthenia gravis is an autoimmune disease produced by antibodies against postsynaptic antigens at the neuromuscular junction, which often presents as ptosis and double vision that worsens as the day wears on. A history of fluctuating weakness can usually be elicited, which on further investigation generally represents fatigability with activity rather than fixed weakness. A more rapid onset of symptoms can also occur, where a patient may have first time symptoms that develop over hours to days following a body stressor such as an infection that triggers presentation of this autoimmune condition. The degree of weakness is highly variable, both from day to day and muscle to muscle. Oculobulbar symptoms are often a feature in the majority of patients with primary autoimmune myasthenia gravis. Around 80 % of patients with myasthenia gravis have antibodies directed against the acetylcholine receptor, 5 % present antibodies against muscle-specific tyrosine kinase, and about 15 % are seronegative, although new antibodies are continually being uncovered in this group of patients. Early-onset myasthenia gravis (under the age of 50 at disease onset) is more frequent among females with thymic hyperplasia, while late-onset myasthenia gravis has been associated with thymoma and more severe disease manifestations.

Prognosis and Therapy

In patients with myasthenia gravis in the absence of cancer, the prognosis is favorable. Cholinesterase inhibitors (e.g., pyridostigmine) are used for symptom relief. Thymectomy may lead to improvement in patients and decrease the overall amount of immunosuppressive needed in managing symptoms. The mainstay of therapy is immunosuppression (steroids and long-term immunosuppressants) and more recently eculizumab for refractory acetylcholine receptor positive myasthenia gravis, with plasma exchange and IVIG used in the treatment of myasthenic exacerbations and crises.

Clinical Features

The periodic paralyses are autosomal dominant neuromuscular disorders associated with mutations in skeletal muscle sodium, calcium, and potassium channels. Attacks of muscle paralysis are caused by sarcolemmal depolarization resulting in sodium channel inactivation with reduced fiber excitability. These are often triggered by behavior or diet and may last minutes to hours or days. Certain conditions are associated with alterations in serum potassium levels. Among the periodic paralyses, the most common is hypokalemic periodic paralysis, with an estimated prevalence of 1 per 100,000 individuals; it is associated with mutation and calcium channels in about 60 % of families and with sodium channels in about 20 %. It usually starts in childhood, with attacks of weakness typically lasting hours to days, often triggered by carbohydrate ingestion. In hyperkalemic periodic paralysis, also associated with sodium channel mutations, attacks typically occur after (not during) exercise and do not last as long (minutes to hours). Ocular and respiratory muscles are usually spared. Although the frequency of attacks in both types of periodic paralysis tends to decrease with age, many patients develop permanent weakness associated with vacuolar muscle fiber degeneration. Fatal cardiac arrhythmias may complicate paralytic attacks in some individuals.

Pathologic Features

Except for patients in whom fixed weakness with vacuolar changes has developed, muscle biopsy specimens usually appear normal by H&E staining. Occasionally, tubular aggregates may be visible as bluish granular cytoplasmic inclusions ( Fig. 11.2A ).

Prognosis and Therapy

Progression to permanent fixed weakness with myopathic changes occurs in a minority of patients and is more common with the hypokalemic variant. Treatment of acute attacks depends on the serum potassium level. Patients with hyperkalemic paralysis may respond to a single dose of acetazolamide and eating high-carbohydrate foods, whereas oral potassium is the treatment of choice for hypokalemic attacks. Dichlorphenamide, also an oral carbonic anhydrase inhibitor, is also available to treat primary hyperkalemic and hypokalemic periodic paralysis.

MYOTONIC DYSTROPHY, TYPE 1

Clinical Features

Myotonia is defined as delayed relaxation after muscle contraction. Patients often complain of stiffness that improves after repeated contractions (“warm-up phenomenon”). Myotonic dystrophy type 1 is unusual among the primary muscle diseases in that patients generally present with distal rather than proximal extremity weakness and wasting. Finger flexor weakness, similar to that seen in patients with inclusion body myositis, is often prominent. Temporalis muscle wasting with ptosis leads to a distinctive “hatchet face” appearance. Myotonic discharges on electromyography support the diagnosis, which can be confirmed by genetic testing. Although patients classically come to medical attention in early adulthood, the age at diagnosis and the severity of the disease correlate with the size of an unstable trinucleotide repeat expansion. Type I myotonic dystrophy (DM1) shows striking changes in presentation over generations, with age at onset typically decreasing by 20 to 30 years per generation progressing from the mild late-onset form to congenital cases in only three generations. Infants with large (greater than 1000 repeats) expansions present with neonatal hypotonia. These severe congenital cases nearly always arise from trinucleotide expansion during oogenesis within an affected mother, although rare cases of large spermatogenic expansion have been reported. In addition, age-dependent somatic expansion markedly complicates genotype phenotype correlations.

Additional clinical features of DM1 include heart block, cardiomyopathy, cataracts, hypersomnia, low IQ, gonadal atrophy, diabetes, frontal balding (in both males and females), swallowing difficulties, and constipation.

Prognosis and Therapy

The severity of the disease correlates directly with the size of the trinucleotide repeat expansion. The most common cause of death is respiratory failure secondary to pneumonia, diaphragmatic weakness, or both. Cardiac arrhythmias, usually secondary to atrioventricular block, are the second leading cause of death. Although indications for pacemaker placement are not clearly defined, abnormal PR intervals or documented dysrhythmias (or both) should prompt referral to a cardiologist.

Clinical Features

Also referred to as proximal myotonic myopathy, DM2 often presents in middle-aged adults with slowly progressive muscular weakness similar to that seen in many other myopathic diseases. Muscle pain is commonly present. To complicate matters further, myotonia may be both subtle and fluctuating, and patients may show hypertrophy of calf muscles. The typical facial wasting seen in DM1 is not present, and cataracts may be missed or not felt to be connected with the muscle weakness.

Prognosis and Therapy

DM2 generally progresses slowly and does not occur as a congenital myopathy. As with DM1, however, cardiac arrhythmias may occur, and thus preventative measures may be lifesaving. In addition, a correct diagnosis of DM2 may avoid the inconvenience and expense of repeated muscle biopsies.

Clinical Features

The core myopathies are the most prevalent subgroup of congenital myopathies, with clinical manifestations ranging from apparent normalcy to severe weakness resulting in the need for ambulatory assistance. Genetic variants causing core myopathies primarily affect proteins involved in excitation-contraction coupling, either by altering calcium transits between the sarcoplasmic reticulum and sarcoplasm or by disrupting the structure of the sarcomere. Ineffective excitation-contraction coupling causes muscle weakness and is associated with the formation of mitochondria depleted core lesions. Typical presentations include infant hypotonia and developmental delay in early childhood, with prominent involvement of limb and axial muscles. Initially, the weakness tends to be slowly progressive or static, but often improves with time (which may be responsible for an appearance of anticipation). Orthopedic abnormalities are common, particularly scoliosis and congenital hip dislocation. In typical ryanodine receptor 1 ( RYR1 ) mutation-associated central core disease (CCD), respiratory weakness and cardiomyopathy are rarely encountered. Malignant hyperthermia is highly associated with RYR1 mutation-associated central core and multi-minicore disease independent of the degree of muscle weakness. Patients with SEPN1 multi-minicore disease commonly manifest severe respiratory weakness and more severe scoliosis than patients with RYR1 -associated diseases.

Prognosis and Therapy

Functional improvement is common even in severe cases, arguing for aggressive supportive therapy and avoidance of stresses that might trigger episodes of malignant hyperthermia. Recent studies of SEPN1 -related myopathy have implicated oxidative stress as the primary factor responsible for muscle impairment, which may portend effective antioxidant therapies.

Clinical Features

Nemaline myopathy was one of the first congenital–structural myopathies described and is a well-known cause of infantile hypotonia (the “floppy infant”). In these babies, prominent facial and respiratory weakness helps distinguish nemaline myopathy from the many other causes of infantile hypotonia. Nemaline myopathy may be caused by mutations in at least 13 genes, and some cases are still molecularly unresolved. The most frequent genetic cause of autosomal recessive nemaline myopathy is a mutation in the nebulin gene, whereas heterozygous pathogenic variants in the α-skeletal actin gene are the most prevalent cause of autosomal dominant nemaline myopathy. Clinical phenotypes range from severe neonatal forms expressing the fetal akinesia sequence to sporadic late-onset nemaline myopathy (SLONM) with isolated neck extensor weakness (the dropped-head sign), dysphagia, and/or respiratory insufficiency. Thus the pathologist must always peruse the muscle biopsy specimen for these sometimes subtle, but distinctive, cytoplasmic structures. This especially applies to biopsies containing very small fibers, as rods may only be apparent under high power magnification or in plastic-embedded sections.

Pathologic Features

Abnormal variation in fiber size is often present, and atrophy or hypotrophy of type I muscle fibers is common. There may also be hypertrophy of type II fibers, resulting in fiber type disproportion. Careful examination of atrophic fibers may reveal focal regions of increased refractivity ( Fig. 11.3A ).

NEMALINE MYOPATHY—PATHOLOGIC FEATURES

Microscopic Findings

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  Atrophic fibers without grouping; may contain small subsarcolemmal areas of increased refractivity

Histochemical Findings

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  Trichrome: reddish-purple thread-like inclusions within the sarcoplasm, often within atrophic fibers

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  Oxidative enzymes: areas with rods may appear core-like

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  ATPase: type 1 fiber predominance and atrophy/hypotrophy

Ultrastructural Features

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  Intracytoplasmic (and rarely intranuclear) rod-shaped structures composed of Z-band–like material, often accompanied by sarcoplasmic disruption

Genetics

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  At least 13 different genetic diseases, including autosomal recessive, autosomal dominant, and de novo autosomal dominant

Immunohistochemical Features

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  Sarcoplasmic rods react with antibodies to αβ-actinin

Pathologic Differential Diagnosis

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  Nemaline bodies may occur at normal myotendinous junctions, in normal extraocular muscles, in aging muscle, and occasionally in a variety of other inherited or acquired neuromuscular disorders, including CCD and inflammatory myopathies

Prognosis and Therapy

The classic neonatal form of the disease carries a 20 % mortality rate, usually secondary to respiratory failure during the first year of life. The other 80 % of these infants show clinical stabilization or even improvement, thus underscoring the value of aggressive supportive therapy. Later onset cases tend to be less severe, but SLONM may be associated with severe disability and even death. There is currently no curative treatment, but supportive management aimed at maintaining muscle strength, mobility, joint movements, and independence in activities of daily living to exercise and physiotherapy is important, as is regular monitoring of respiratory function and orthopedic problems, especially scoliosis.

Clinical Features

To date, acute quadriplegic myopathy has been reported exclusively in the critical care setting, which explains its alternative name: critical illness myopathy. This myopathy is usually recognized when a critically ill patient cannot be weaned off the ventilator because of diffuse flaccid paralysis, including paralysis of the diaphragmatic and intercostal muscles. Two of the three following are usually required to cause this disorder: corticosteroid therapy, neuromuscular blockade, and severe systemic illness such as sepsis.

Prognosis and Therapy

On cessation of corticosteroid therapy or neuromuscular blockade (or both), recovery of muscle strength occurs within 3 weeks in approximately 50 % of patients; the majority of the remaining patients regain normal strength within a year. Treatment is supportive. Prevention is recommended and is achieved through the restriction of corticosteroid use in critically ill patients for disorders in which the corticosteroids show a clear and significant improved patient outcome.

Clinical Features

As the name implies, these diseases usually do not show symptomatology until after the age of 40, and most affected patients do not come to medical attention until they are in their 50s, 60s, or even older—in other words, the same age as patients suffering from inclusion body myositis. To further complicate the differential diagnosis, patients with myofibrillar myopathies often manifest predominantly distal weakness, though more often in their lower extremities (unlike patients with inclusion body myositis, where distal weakness is usually confined to upper extremities). Proximal muscles may be affected, as exemplified by the integral Z-disc protein, myotilin, the mutation of which underlies both late-onset myofibrillar myopathy and limb-girdle muscular dystrophy 1A (LGMD1A). Depending on the specific Z-disc protein involved, families with late-onset myofibrillar myopathies may manifest cardiac symptoms as well as peripheral neuropathy.

Prognosis and Therapy

Weakness in these diseases tends to be very slowly progressive. Therapeutic efforts are supportive and preventative, especially in families with systemic complications.

Clinical Features

The original description of early-onset myofibrillar myopathy secondary to mutations involving desmin included progressive distal or proximal weakness associated with cardiomyopathy. Common autosomal dominant mutations manifest during early and middle adulthood. Rare autosomal recessive mutations have been reported and present during childhood. Clinical manifestations vary widely, but usually include slowly progressive weakness, respiratory insufficiency, and cardiomyopathy with conduction block. Early-onset myofibrillar myopathies resulting from proteins that interact with desmin (such as αβ-crystallin) are increasingly being recognized, but as their neuromuscular manifestations are currently not easily distinguishable from those resulting from desmin mutations, myopathies primarily involving the intermediate filament system of skeletal muscle are usually collectively referred to as desminopathies.

Pathologic Features

Similar to late-onset myofibrillar myopathies, desminopathies show increased fiber size variability, internalized nuclei, rimmed vacuoles, and sarcoplasmic aggregates ( Fig. 11.4A ).

EARLY-ONSET MYOFIBRILLAR MYOPATHY—PATHOLOGIC FEATURES

Microscopic Findings

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  Myopathic features: fiber size variability, internalized nuclei, degeneration and regeneration of muscle fibers, endomysial fibrosis, rimmed vacuoles

Histochemical Findings

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  Trichrome may show red or blue sarcoplasmic aggregates of varying morphologies

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  “Rubbed-out” fibers may be seen on oxidative enzyme stains

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  Aggregates react with anti-desmin antibodies, which also may show plaque-like subsarcolemmal staining

Ultrastructural Features

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  Myofibrillar disorganization

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  Z-disc streaming

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  Granulofilamentous inclusions

Genetics

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  In addition to numerous autosomal dominant and recessive desmin mutations, patients with mutations in αβ-crystallin demonstrate indistinguishable myopathology

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  Many patients have no family history of muscle disease and may also lack demonstrable genetic abnormalities

Pathologic Differential Diagnosis

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  Late-onset myofibrillar myopathies (Z-disc diseases)

Prognosis and Therapy

No specific treatments are currently available, but complications may be preventable. Investigation and treatment of cardiac conduction defects, transplantation for cardiomyopathy, and respiratory support are critical if early mortality is to be avoided.

Clinical Features

Duchenne muscular dystrophy becomes clinically apparent in early childhood. Initially, these young boys are clumsy and have trouble running; later, they have difficulty climbing stairs. Hip and knee extensor weakness manifests as the Gowers sign, whereby the child climbs up his thighs with his hands to arise from a lying or sitting position. Although calf hypertrophy is considered to be one of the hallmarks of Duchenne muscular dystrophy, it is not specific. Progressive, mainly proximal, muscle weakness tends to remain relatively stable until the age of about 7 years, when more rapid progression becomes apparent, leading to wheelchair dependence in most boys by the age of 12 years, followed by scoliosis, loss of upper limb function, respiratory insufficiency, and cardiomyopathy.