BACKGROUND Focal atrophy of an individual muscle or group of muscles, often encountered clinically, may create diagnostic and therapeutic

challenges. A wide variety of neurologic disorders may present with focal muscular atrophy (FMA). FMA also may be secondary to nonneurologic conditions, leading to disuse of part of a limb. PATHOPHYSIOLOGY The organ ultimately affected is the muscle, although the pathology may be anywhere along the lower motor neuron (LMN) or, at times, secondary to nonneurologic disorders. Etiologic factors include the following:

Infection Trauma Inflammation Spinal cord disorders Vasculitis Entrapment Altered immune mechanisms Toxins Physical agents, such as electrical or radiation injury Genetic and enzyme defects Monomelic amyotrophy has been reported more often in India[10] , Korea[11] , and Japan than in other countries. In a hospital-based study from India, among 110 patients with anterior horn cell disease, 10.9% had progressive muscular atrophy; 1.8%, PPMA; and 22.7%, monomelic amyotrophy.[12]

Mortality/Morbidity

Most disorders that cause FMA are benign and do not lead to higher-than-normal mortality rates. Most patients do not suffer significant disability, except when the FMA involves an entire limb, becomes generalized, or has an acute onset.
Race

Most conditions that cause FMA do not have any racial predilection. The geographic variations of some of these disorders probably reflect environmental conditions rather than genetic predisposition.
Sex

Bulbospinal muscular atrophy (an X-linked disorder) involves only males. Monomelic amyotrophy is more common in men. PPMA is more frequent in women.
Age

Disorders such as polio and monomelic amyotrophy are more common in younger people.

HISTORY
Focal muscular atrophy (FMA) has various causes and, hence, various signs and symptoms.

Muscle wasting is probably the presenting symptom when the onset is insidious (see images below). Weakness may not be a primary symptom in these patients.

A man with neuralgic amyotrophy presenting with wasting of deltoids involving the right side more than the left

. A middle-aged man with (atypical) anterior horn cell disease presenting with wasting of the right quadriceps.

Muscle weakness occurs when the onset is more abrupt. o Distal weakness in the upper limbs may manifest with the following difficulties: opening jars, holding tightly to a pencil, typing, fingering a musical instrument, buttoning a shirt, or tying shoelaces. o Proximal weakness in upper limbs may manifest with difficulty in raising the arms or reaching for high objects. o Weakness of lower limb muscles may result in the following difficulties: walking, climbing stairs, walking on uneven surfaces, and stumbling over small objects. Muscle twitching (fasciculations) occurs when anterior horn cells or proximal roots are involved. Muscle cramps, commonly experienced in the gastrocnemius muscles, are characterized by sudden, brief, intense muscle pain; a strong, hard, palpable muscular contraction; and immediate relief by stretching the muscle. Sensory symptoms (eg, pain, numbness, tingling or burning sensation) suggest involvement of roots, plexi, or peripheral nerves. Trophic changes may be seen when small fibers of the peripheral nerve are involved or a defect in pain, temperature, or jointposition sensation is noted.

Systemic symptoms suggest diabetes, arthritis, articular injury, collagenosis, malignancy, abuse of prescription or nonprescription drugs, or intravenous (IV) drug abuse. Geographic preponderances of monomelic amyotrophy, polio, and leprous neuropathy have been recognized. Consider such diseases in immigrants from the appropriate geographic regions. A history of affected family members may suggest genetic disorders such as spinal muscle atrophy (SMA) or a familial clustering due to infectious disease or environmental mechanisms. Past history of polio, trauma, radiation, electrical injury, malignancy, or lymphoma should suggest an etiology for FMA. Occupational exposure to toxins may lead to FMA.

PHYSICAL
Signs vary depending on the causative disorder.

General physical examination may reveal evidence of arthritis or other deformities. Examination of the cranial nerves may reveal evidence of tongue wasting, which suggests amyotrophic lateral sclerosis (ALS) or other diseases that involve the bulbar musculature. o The pattern and distribution of muscle wasting and weakness may localize the lesion to a peripheral nerve or plexus or root. Muscle hypertrophy may be noted in myopathic disorders as well as in neurogenic disorders. o Fasciculation may occur in cases of anterior horn or proximal root involvement. o Sensation is normal in disorders that affect only the anterior horns, but it may be impaired when the root/plexus/peripheral nerve is affected. The distribution of sensory loss may have a localizing value. The deep tendon reflexes (DTRs) may be brisk or exaggerated in spinal lesions or in ALS. o DTRs may be normal in muscle diseases.

DTRs may be absent in a root/plexus/nerve lesion. Footdrop gait and inability to walk on the heels reveal weakness of the foot dorsiflexors. Difficulty in walking on the toes and hopping on the toes of one foot are signs of calf muscle weakness. Toe-walking indicates contracture of the Achilles tendon. Limping gait is a sign of unilateral muscle weakness or arthritis involving the lower limb(s). Thickened peripheral nerve(s) and anesthetic skin lesions may suggest leprous neuropathy. Foot deformity implies weakness of the intrinsic muscles of the feet. Deformity or tenderness of the spine reveals diseases of the spinal cord or roots that are secondary to vertebral pathology. Scoliosis may occur in distal SMA.

CAUSES
FMA can arise from several anomalies that affect the LMN.

Diseases involving the anterior horn cells o Infections Poliomyelitis Poliolike viruses (eg, neuronopathy following acute hemorrhagic conjunctivitis caused by EV70 virus) PPMA Retroviral infections such as HIV or human T-cell lymphotrophic virus (HTLV)[13] o Anterior horn cell diseases (noninfective) Syndromes mimicking ALS Early motor neuron disease SMA and its variants Monomelic amyotrophy Anterior horn cell degeneration in Parkinsonism and other degenerative disorders

Focal spinal lesions Syringomyelia Intramedullary tumors Vascular lesions of spinal cord Trauma that causes a syrinx or hematomyelia Postinfectious radiculoneuropathies o Miscellaneous Inherited enzyme defects - Hexosaminidase A deficiency Immunologic disorders - Dysproteinemia, anti-GM1 antibody Metabolic - Diabetes Toxins -Lead, mercury Endocrine - Thyroid disorders Physical - Radiation and electrical injuries Paraneoplastic - Subacute motor neuronopathy associated with cancer or lymphoma (especially Hodgkin disease) Spinal root lesions o Intervertebral disk prolapse o Root avulsion o Tumors - Meningioma, schwannoma o Spinal dysraphisms with myelomeningocele, low tethering of the cord, mesenchymal rests, or lipomas o Radiation radiculopathy o Ankylosing spondylitis o Diabetes mellitus Brachial and lumbosacral plexus lesions o Malignant invasion o Thoracic outlet syndrome o Trauma o Obstetric injuries o Tomaculous plexopathy o Psoas hemorrhage due to anticoagulants or other causes o Psoas abscess o Radiation o Brachial neuritis (neuralgic amyotrophy) o Familial brachial plexopathy o Diabetes
o

Vasculitis o Intraarterial injections (gluteal and iliac arteries) o Herpes zoster o Idiopathic lumbosacral plexopathy Peripheral nerve diseases o Peripheral nerve injuries - External compression, partial or complete transection o Entrapment - Carpal tunnel, suprascapular entrapment o Ischemia (vasculitis) o Multifocal motor neuropathy with conduction block and high titer of anti-GM1 antibodies o Leprosy o Diabetic mononeuropathy Muscle diseases o Sarcoid myopathy o Quadriceps myopathy o Focal myositis and inclusion body myositis o Injection myopathy [14] o Skeletal muscle lymphoma [15] o Central core disease of muscle o Muscular dystrophies o Myotonic dystrophy o Congenital absence of muscle Disuse atrophy - Secondary to arthritis, fractures, periarthritis other injuries FMA confined to bulbar muscles o Bulbar palsy due to ALS: Limb involvement eventually occurs in most cases. o Hereditary autosomal-dominant bulbar palsy: The bulbar weakness is progressive, but limb involvement is rare. o Postpolio syndrome occurring in patients with a history of bulbar involvement during acute polio o Diseases involving the hypoglossal nerve and motor component of the trigeminal nerve o Structural brainstem lesions such as tumor, stroke, or syringobulbia
o

The most frequent causes of FMA are the following. A brief discussion of some of the most common causes follows this list. o Disuse atrophy o Traumatic root lesions, plexus injuries, brachial and lumbosacral plexopathies o Mononeuropathy due to trauma, diabetes, vasculitis, infection (leprosy), or entrapment o Polio, PPMA, monomelic amyotrophy, early motor neuron disease, variants of SMA, and syringomyelia Postpolio progressive muscular atrophy o New symptoms and signs can occur many decades after the acute illness in up to 40% of survivors of acute paralytic poliomyelitis. Symptoms and signs similar to PPMA have also been reported in individuals without preceding paralytic poliomyelitis (among those who have had nonparalytic polio). o The muscle-related effects of postpolio syndrome are possibly associated with an ongoing process of denervation and reinnervation, reaching a point at which denervation is no longer compensated for by reinnervation.[18, 19] o Postulated pathogenetic mechanisms include persistent active poliovirus infection, superimposition of the normal aging process on a depleted motor neuron pool, inflammatory process, altered immunity, or increased vulnerability of poliovirus-damaged neural tissue to new infections. GM1 antibodies and serum insulinlike growth factor-1 are probably not involved in the pathogenesis of PPMA.[18, 20] o Proteomic analysis of the CSF of persons with PPMA displayed a disease-specific and highly predictive (P =0.0017) differential expression of 5 distinct proteins: gelsolin, hemopexin, peptidylglycine alpha-amidating mono-oxygenase, glutathione synthetase, and kallikrein 6, respectively, in comparison with the control groups. These 5 proteins require further evaluation as candidate biomarkers for the diagnosis and development of new therapies for PPMA patients.[21]Inflammatory markers such as

serum TNF-alpha, IL-6, and leptin levels are abnormally increased in PPMA patients.[22] Clinical features include the following: Fatigue and loss of independence in activities of daily living (ADLs) Development of new-onset asymmetric weakness and/or atrophy in muscles that were affected previously or were unaffected by polio New onset or worsening of muscle twitching or cramping Pain Pyramidal signs distinctly lacking Bulbar features, such as dysphagia and dysphonia, seen only as residua among patients who showed such involvement in the disease's acute stage Progression much slower than in classical ALS Postpolio syndrome patients with predominant fatigue may form a subgroup who are younger, had shorter polio duration, more pain, higher body mass index, lower quality of life, and more physical and mentally fatigue. Criteria for diagnosis Documented history of acute paralytic poliomyelitis with incomplete to nearly complete neurologic and functional recovery Period of neurologic and functional stability lasting at least 15 years New onset of asymmetric weakness and/or atrophy in muscles that were affected previously or were clinically unaffected by polio New onset or worsening of muscle twitching or cramping and pain Electrophysiologic features of acute denervation superimposed on chronic denervation-reinnervation No other medical, neurologic, orthopedic, or psychiatric cause for weakness

Features that distinguish PPMA from ALS Age of onset of PPMA is earlier than that of ALS. Females are affected with PPMA more often than ALS. Motor involvement is usually focal or multifocal and asymmetric. The frequency and distribution of fasciculations are sparse. Bulbar and respiratory involvement are absent, except in survivors of bulbar cases. Corticospinal tract signs are absent. Accompanying pain is common. Progression is slower and fatal outcomes are rare in PPMA.

Monomelic amyotrophy o This disorder is defined in several reports as a benign disorder characterized by wasting that is confined to a single limb or part of a limb.[24] o In India, Korea, and Japan, such occurrences are termed benign focal amyotrophy, Hirayama disease, wasted leg syndrome, or monomelic amyotrophy. Isolated reports of this disorder also have come from Brazil, France, Germany, Italy, Spain, Turkey, Poland, and Canada. o The etiology is unknown. Degenerative, infectious, and ischemic mechanisms have been postulated.[30] A flexion myelopathy has been postulated on the basis of MRI studies, where the dura and spinal cord may be compressed repeatedly during neck flexion, possibly inducing an ischemic myelopathy.[31, 32] Venous congestion in the spinal canal as demonstrated in phase contrast magnetic resonance (MR) angiography may also have a role in promoting anterior horn damage.[33] o Although some authors consider this disorder as a variant of SMA with a focal emphasis and a benign course, no deletions of the survival motor neuron gene (as are found in proximal SMAs) have been reported.[34] Monomelic amyotrophy was associated with the 7472 insC mutation in the mtDNA tRNA (Ser(UCN)) gene in one family with a correlation between mutation load and clinical severity.[35]

o o

HyperIgEaemia is often associated with Hirayama disease, although a causal relationship has not been established. [36] The term monomelic amyotrophy should be reserved only for cases of focal muscle wasting that is confined to a single limb without secondary causes. The disorder is generally sporadic, involving young men aged 18-50 years. Gradual in onset, the course may be nonprogressive or feature initial progression for 1-5 years followed by a plateau state. Spread to the other limb or limbs has occasionally been documented. Recurrent forms and familial occurrences have been reported.[37] Clinical features include asymmetrical proximal or distal atrophy of a single upper or lower limb; fasciculations; absence of sensory, bulbar, or pyramidal signs; and no history of polio. Typically, the patient or the patient's family note rather abrupt unilateral weakness and atrophy of the hand and forearm muscles (C8, T1, and less often C7). Oblique atrophy, where a normal brachioradialis (C5/C6) dominates the atrophied forearm, is a characteristic feature (see image below). Sensation is normal, DTRs are normal, and no pyramidal signs are present.

Clinical photograph of a subject with monomelic amyotrophy showing wasting of left forearm. Note the characteristic feature of oblique atrophy, where a normal brachioradialis dominates the atrophied forearm.
o

Despite marked wasting, patients may have little to no weakness. Electrophysiologic, radiologic, and muscle histopathologic findings indicate a chronic focal anterior horn cell disease.

In the early stages of the disease, no clinical or laboratory findings distinguish it from motor neuron disease. Prolonged observation may be required to confirm the diagnosis.

Spinal muscular atrophies o Focal forms of SMA often are isolated cases. When they are hereditary, the genetic profile is highly heterogeneous.[38, 39, 40] o Associated features (eg, gynecomastia and testicular atrophy in bulbospinal muscular atrophy; pes cavus in distal SMA) may help pinpoint the diagnosis of the subtypes. o The disease does not necessarily evolve, but it may progress to a generalized form. o Focal forms may be symmetric, asymmetric, spinal-bulbar, or multisegmental. o Bulbospinal muscular atrophy (Kennedy disease) This X-linked recessive disease is associated with an increase in the number of polymorphic tandem CAG repeats in exon 1 of the androgen receptor (AR) gene on the proximal long arm at Xq11 locus. The aggregation of the expanded repeat AR, in the residual motor neurons in the brainstem and spinal cord, rather than playing a pathogenic role, likely reflects the insoluble nature of the misfolded AR protein.[41] Proteolytic processing of the expanded AR protein at various stages of its metabolism may contribute to cellular toxicity through the enhancement of AR protein insolubility, and potentially through the disruption of normal proteolytic degradation processes. Transgenic mice carrying the full-length human AR gene with an expanded polyQ tract demonstrate neuromuscular phenotypes, which are profound in males. Their bulbospinal muscular atrophylike phenotypes are rescued by castration and aggravated by testosterone administration. Leuprorelin, an LHRH agonist that reduces testosterone release from the testis, inhibits nuclear accumulation of mutant AR proteins, resulting in the rescue of motor dysfunction in the male transgenic mice. However, flutamide, an androgen antagonist

promoting nuclear translocation of the AR gene, yielded no therapeutic effect. The degradation and cleavage of the AR protein are also influenced by the ligand, contributing to the pathogenesis. Testosterone appears to be the key molecule in the pathogenesis of Kennedy disease as well as the main therapeutic target of this disease.[42] Muscle cramps on exertion and gynecomastia often precede weakness in the pelvic girdle, which develops between the third and fifth decades. Facial, bulbar, and distal limb involvement may follow. Perioral fasciculations, hand tremors, noninsulin-dependent diabetes mellitus, and infertility are common. Nerve conduction may reveal sensory nerve action potential abnormalities in addition to reduced amplitude of compound muscle action potentials (CMAPs), suggesting degeneration of the dorsal root ganglia in addition to the anterior horn cells. Needle electromyography (EMG) reveals acute and chronic motor axon loss (with the latter predominating). On needle EMG examination of the facial muscles, grouped repetitive motor unit discharges, which are present at rest but become prominent with mild activation of the facial muscles, may occur.[43] The age of onset and clinical severity of the disease often correlate with serum testosterone and gonadotrophin levels and the number of CAG repeats in the AR gene. DNA analysis is now commercially available to help identify singleton males and carrier females. The lifespan is reduced only minimally.

Distal spinal muscular atrophy This disorder is transmitted by autosomal-dominant and recessive genes in about half of cases. The remaining cases are sporadic. The most common presentation is at or soon after birth. Distal wasting, weakness, and hypotonia start in the legs and later involve the arms. Pes cavus is frequent.

The disorder is usually mild and evolves slowly or even stabilizes, except in the adult-onset recessive type, which is severe and rapidly progressive.

Amyotrophic lateral sclerosis and syndromes that mimic ALS o ALS: A small percentage of patients with adult-onset motor neuron disease have one of the restricted subtypes, which traditionally are included within the clinical spectrum of ALS versus progressive muscular atrophy (the pure LMN form) versus progressive bulbar palsy (the pure bulbar form). o In the El Escorial terminology, none of these subtypes would be considered "definite" or "probable" but instead, "suspected" or "possible" ALS. o Most patients who are diagnosed initially with a restricted subtype evolve clinically to classical ALS. o Postradiation motor neuron disease and plexopathy This syndrome, which is due to degeneration of lumbar or cervical motor neurons, occurs months to years after irradiation of the neck, abdomen, or pelvis for malignant disease. Muscle atrophy, fasciculations, weakness, and areflexia in the legs may progress rapidly. The syndrome occurs in about 2-10% of susceptible patients, especially in patients who receive more than 3.3 Gy to the spinal cord. It results from vascular damage and white matter necrosis in the spinal cord. In postradiation plexopathy, patients develop asymmetric and often painless muscle weakness and atrophy. EMG findings include characteristic spontaneous myokymic discharges from involved muscles. o Multifocal motor neuropathy with conduction block and high-titer serum anti-GM1 antibodies This motor syndrome is more common in males. This disorder typically is associated with atrophic hand weakness. No bulbar or upper motor neuron (UMN) signs are

noted. Conduction block in motor nerves and high serum titers of anti-GM1 antibodies are present. Multifocal motor neuropathy also may occur without elevation of anti-GM1 antibody titers. o Hexosaminidase deficiency Juvenile SMA and a syndrome that mimics ALS have been described with hexosaminidase deficiency (primarily in Ashkenazi Jews). The onset is usually in childhood or adolescence with features of psychosis, dementia, ataxia, stuttering dysarthria, and peripheral neuropathy. Hexosaminidase A deficiency can be demonstrated in serum, leukocytes, or skin fibroblasts. Rectal biopsy specimens show characteristic membranous cytoplasmic bodies in ganglion cells of the mucosa. The disorder is much more slowly progressive than classical ALS. o Immune-mediated syndromes that mimic ALS Serum monoclonal gammopathy is encountered more frequently among patients with motor neuron disease than in neurologic disease control patients. The frequency of LMN disease that resembles progressive muscular atrophy is more common in these patients than in motor neuron disease that is unassociated with gammopathy. Muscle disorders o Focal myositis This disorder may present with focal or asymmetric weakness and wasting. The myopathy may progress or remain stable. Serum creatine phosphokinase (CPK) may be elevated, and EMG shows brief, small-amplitude, motor unit potentials and fibrillations in the affected muscles. Immunosuppressive therapy may arrest progression.
o

Infective myositis: Localized infections of the muscle as in tropical pyomyositis or tuberculous abscess of the muscle may

mimic a focal myositis . The disorder can be excluded by the presence of constitutional signs, findings from muscle ultrasound or MRI, and findings from aspiration of pus or by exploration and muscle biopsy.
o

Inclusion body myositis The presence of slowly progressive, asymmetric quadriceps and wrist/finger flexor weakness in a man older than 50 years strongly suggests this diagnosis. Inclusion body myositis is slowly progressive and does not respond well to immunosuppressive medications. Sarcoid myopathy Consider muscular involvement by sarcoid in the differential diagnosis of focal muscle disease, especially in a patient with a known history of sarcoid. Muscular sarcoid may be nodular, atrophic myopathic or acute myositic. Muscle involvement can be focal, multifocal, or generalized. Patients may present with focal muscle pain, tenderness, and weakness. Atrophy of the involved muscles occurs with chronic disease. Asymptomatic granulomas may be palpated within the muscle. Rarely, a superimposed neuropathy is also evident. Most patients have coexisting pulmonary symptoms and lymphadenopathy. The presence of typical bilateral hilar adenopathy on a chest radiograph and abdominal findings (eg, hepatosplenomegaly and retroperitoneal adenopathy) may help establish the diagnosis. Ultrasonically guided biopsy may be necessary for definitive diagnosis. Many patients with sarcoidosis have granulomas in the muscle, although signs and symptoms of muscle involvement may be absent. Serum angiotensin-converting enzyme (ACE) levels often are elevated, and these patients are frequently anergic to tuberculin skin testing. Chest films usually demonstrate hilar lymphadenopathy and parenchymal

involvement of the lungs. Serum CPK is usually normal or only mildly elevated. EMG may appear normal or show myopathic or mixed myopathic and neurogenic features. Treatment usually is focused on other systemic manifestations, as the myositis is typically asymptomatic. Corticosteroids are effective in treating the myositis.
o

Injection myopathy Deltoid and/or gluteal fibrotic contractures are seen in some patients who receive repeated intragluteal or intradeltoid injections. FMA and weakness of the involved muscles result. Nearly one third of the patient's siblings may be affected by the same fibromuscular disorder. EMG reveals myopathic changes in the affected muscles. Repeated injection injuries and myotoxicity, resulting in multifocal myositis and abnormal control of collagen formation, could be important pathogenic factors. Congenital absence of muscle (although not an atrophy in a strict sense) may result in focal thinning. It may be unilateral or bilateral, limited to a single muscle or group of muscles. The course is stationary. The most commonly missing muscles include the pectoralis, trapezius, serratus, and quadriceps. Muscular dystrophies FMA also may be a feature in certain muscular dystrophies. In fascioscapulohumeral dystrophy, the arms have a "Popeye" appearance with preservation of the forearms and marked wasting of the upper arms. In limb girdle dystrophy, wasting of the upper portion of the deltoid with preservation of lower portion gives an unusual muscle configuration.

In myotonic dystrophy, wasting of the temporalis and masseter muscles and atrophy of the neck muscles may occur.

Mononeuropathies Mononeuropathies result from pathology in a peripheral nerve that is secondary to trauma, leprosy, vasculitis, diabetes, or entrapment. These are common causes of FMA. Common examples of FMA due to entrapment are thenar muscle wasting in carpal tunnel syndrome, hypothenar and interossei wasting in ulnar nerve entrapment at the elbow, infraspinatus wasting due to entrapment of the suprascapular nerve at the spinoglenoid notch, and muscle wasting in the anterolateral compartment of the leg due to entrapment of the common peroneal nerve at the fibular head.

Neuralgic amyotrophy o Neuralgic amyotrophy (brachial plexus neuritis) is characterized by extreme neuropathic pain and rapid multifocal weakness and atrophy in the upper limb. o Neuralgic amyotrophy has both an idiopathic and hereditary forms. The clinical presentations of idiopathic and hereditary forms are similar except for earlier age of onset and more recurrences in the hereditary form. o The precise pathophysiological mechanisms are still unclear. In 55% of families with familial neuralgic amyotrophy, a point mutation or duplication in the SEPT9 gene on band 17q25 has been reported. A combination of factors, such as an underlying genetic predisposition, a susceptibility to mechanical injury of the brachial plexus (possibly representing disturbance of the epineurial blood-nerve barrier), and an immune or autoimmune response to the brachial plexus, may trigger the attacks.[48] o Evidence from one open-label retrospective series suggests that oral prednisone given in the first month after onset can shorten the duration of the initial pain and leads to earlier recovery in some patients.

Recovery is slow, in months to years, and many patients are left with residual pain and decreased exercise tolerance in the affected limb(s).[49]

DIFFERENTIAL DIAGNOSES

Amyotrophic Lateral Sclerosis Brainstem Gliomas Chronic Inflammatory Demyelinating Polyradiculoneuropathy Congenital Muscular Dystrophy Congenital Myopathies Dermatomyositis/Polymyositis Diabetic Neuropathy Emery-Dreifuss Muscular Dystrophy Endocrine Myopathies Facioscapulohumeral Dystrophy Femoral Mononeuropathy HIV-1 Associated Acute/Chronic Inflammatory Demyelinating Polyneuropathy HIV-1 Associated Multiple Mononeuropathies HIV-1 Associated Myopathies HIV-1 Associated Neuromuscular Complications (Overview) HIV-1 Associated Vacuolar Myelopathy Inclusion Body Myositis Infectious Myositis Kennedy Disease

LABORATORY STUDIES

The choice of investigations depends on the physical signs, symptoms, and clinical impression. Blood counts, erythrocyte sedimentation rate (ESR), serum glucose, serum CPK When clinically indicated Thyroid functions

Rheumatoid factor Serum ACE assay Serum anti-GM1 antibodies Viral studies Screening for toxins or systemic malignancy Cerebrospinal fluid analysis Order lumbar puncture with cerebrospinal fluid (CSF) analysis when clinically or electrophysiologically indicated. CSF proteins may be elevated in multifocal motor neuropathy. Oligoclonal immunoglobulin G (IgG) bands and antibodies to the poliovirus may be detected in the CSF of patients with PPMA.

IMAGING STUDIES

Radiographs Chest - May reveal cervical rib or apical lung lesions or hilar adenopathy Spine - May give evidence of vertebral lesions with secondary involvement of the cord or roots MRI of the spine This study may be useful when a disease of the spinal cord, spine, or roots is suspected. In some patients with monomelic amyotrophy, MRI demonstrates focal and unilateral atrophy in the lower cervical cord, which is limited to the anterior horn region. MRI may also reveal forward displacement of the cervical dural sac and compressive flattening of the lower cervical cord during neck flexion. MRI of the muscles This study can provide information on the pattern of muscle involvement by showing the cross-sectional area of axial and limb muscles. It may demonstrate signal abnormalities in affected muscles secondary to inflammation and edema or replacement by fibrotic tissue.

Some authors have advocated MRI as a guide to decide which muscle to biopsy, although this recommendation is controversial. Muscle ultrasound Ultrasound can help visualize abnormalities such as muscle atrophy due to root, plexus, and nerve lesions. Spontaneous EMG activity correlates closely with abnormal ultrasonographic findings (especially with increased muscular echo intensity). Ultrasonography is considered by some authors to be as sensitive as manual muscle testing and EMG in detecting muscle involvement. However, large studies comparing the sensitivity and specificity of muscle ultrasound and EMG in the diagnosis of neuromuscular diseases are not available.

Screening for systemic malignancy may be appropriate. Test for hexosaminidase A in serum, leukocytes, or skin fibroblasts when deficiency is suspected. Molecular diagnostic tests Bulbospinal muscular atrophy (ie, Kennedy disease) is associated with an increase in the number of polymorphic tandem CAG repeats in exon 1 of theAR gene on the proximal long arm at Xq11 locus. The gene candidates for spinal muscular atrophy include the genes for the survival motoneuron (SMN) and the neuronal apoptosis inhibitory protein (NAIP). Both genes are duplicated on chromosome 5. Genetic mutations have been identified in the major motor neuron diseases, including ALS (SOD1 gene), the hereditary spastic paraplegias, and rarer conditions such as GM2 gangliosidosis (hexosaminidase A deficiency). Patients with hereditary neuropathy with tendency to pressure palsies may have a deletion on chromosome 17p11.2. Xp21 deletion may suggest a diagnosis of Becker muscular dystrophy when the patient presents clinically with a quadriceps myopathy. Electromyography

EMG is useful in differentiating a myopathic from a neurogenic disorder. It can detect anterior horn cell involvement. Findings in a patient with FMA due to atypical anterior horn cell disease can be seen in the images below.

EMG at rest from the right quadriceps muscle of a patient with atypical anterior horn cell disease and isolated atrophy of the right quadriceps; EMG shows spontaneous activity.

EMG on voluntary effort from the right quadriceps muscle of a patient with atypical anterior horn disease and isolated atrophy of the right quadriceps; EMG shows motor unit potentials that exhibit prolonged duration and polyphasia.

EMG on maximal effort from the right quadriceps muscle of a patient with atypical anterior horn disease and isolated atrophy of the right quadriceps; EMG shows an impaired interference pattern.

Paraspinal EMG may be valuable in spinal root lesions. Spontaneous activity (eg, fibrillations, fasciculations) may be seen in ALS and to a lesser degree in SMA and PPMA. Kennedy disease may be characterized by the presence of grouped repetitive motor unit discharges on needle EMG examination of the facial muscles, such as the mentalis muscle, which are present at rest but become prominent with mild activation of the facial muscles, such as with pursing the lips or

whistling. Because these discharges occur with voluntary contraction rather than spontaneously, they are distinguished from myokymic or neuromyotonic discharges.[43] Long-duration, high-amplitude motor unit potentials (which indicate a chronic denervation with reinnervation) are seen in PPMA and, to a lesser extent, in ALS and other anterior horn cell diseases such as SMA and monomelic amyotrophy. Myopathic pattern with fibrillations suggests an inflammatory myopathy.

Nerve conduction studies These studies may reveal evidence of peripheral nerve involvement: mononeuropathy, nerve entrapment, diabetic amyotrophy, and brachial or lumbosacral plexopathies. The abnormalities may include prolonged distal latencies, slowed conduction velocities, reduced amplitude of CMAPs, and evidence of conduction block. The F responses and H reflex studies may be useful in assessing proximal root lesions. Disuse muscular atrophy from immobilization also is associated with a significant reduction in CMAP amplitude, which may vary according to muscle site and function. Unlike other motor neuron diseases, including the spinal muscular atrophies, in Kennedy disease, diffusely low amplitude or absent SNAPs may occur, despite normal sensation on clinical examination. Evoked potentials Somatosensory evoked potentials are usually normal when the disorder involves only the motor system. They may be abnormal when the somatosensory pathway is affected. Serial motor evoked potential (SMEP) recordings can be useful for the early detection of subclinical UMN dysfunction in motor neuron disease, which presents with pure LMN signs. Muscle biopsy, nerve biopsy, or lumbar puncture may be performed when clinically indicated.

HISTOLOGIC FINDINGS
Histologic findings are dependent on the underlying cause. Necropsy in one patient with monomelic amyotrophy (who died of unrelated causes) revealed lesions only in the anterior horns of the spinal cord over a few segments. The anterior horn cells showed shrinkage and necrosis, various degrees of degeneration of large and small neurons, and mild gliosis. The posterior horn, white matter, and vascular system showed no abnormalities. Autopsies of a few patients with PPMA revealed the presence of persistent or new inflammation (lymphocytic infiltrates) in the meninges, spinal cord, and muscles of affected patients. In one of these patients, immunoperoxidase staining demonstrated that the inflammatory infiltrates were virtually pure populations of B lymphocytes. The other histologic features were the presence in spinal cord anterior horns of axonal spheroids and Wallerian degeneration in the lateral columns. No abnormalities were found in the brain. In patients with chronic disease, muscle histology in focal myositis may reveal variable fiber size, degenerating and regenerating fibers, inflammatory foci, vasculitis, and fibroblastic proliferation. In Kennedy disease, the muscle biopsy specimen reveals variability of fiber size with groups of angular atrophic fibers, fiber type grouping, and pyknotic nuclear clumps characteristic of chronic denervation with reinnervation. Nonspecific myopathic features, including increased central nuclei and necrotic fibers, are also seen. The histopathologic hallmark is the presence of nuclear inclusions containing mutant truncated ARs in the residual motor neurons in the brainstem and spinal cord as well as in some other visceral organs. The histologic findings in inclusion body myositis are endomysial inflammation, small groups of atrophic fibers, eosinophilic cytoplasmic inclusions, and muscle fibers with one or more rimmed

vacuoles that are lined with granular material. Amyloid deposition is evident on Congo red staining by using polarized light or fluorescence techniques. Electron microscopy demonstrates 15-21 nm cytoplasmic and intranuclear tubulofilaments. Muscle histology in sarcoidosis is characterized by perivascular noncaseating granulomas consisting of clusters of epithelioid cells, lymphocytes, and giant cells. Muscle histology in injection myopathy may reveal perimysial and endomysial fibrosis with nonspecific degeneration, regenerative changes and, in some cases, partial denervation signs. Electron microscopy reveals that endomysial and perimysial collagen fibrils have lost their normal unimodal diameter distribution. They instead show a broad spectral distribution of diameters, suggesting defective control of collagen formation.

MEDICAL CARE
Treatment of focal muscular atrophy (FMA) varies according to the cause.

The common causes (eg, monomelic amyotrophy, PPMA, SMA) have no specific treatment. When patients with these conditions have disability, the treatment consists of physical and occupational therapy and rehabilitation. A recent report of increase in the SMN2 messenger RNA levels in vivo among 7 of 13 patients with spinal muscular atrophy treated with valproic acid raises possibilities of in vivo activation of causative genes in inherited diseases. Counsel patients concerning the benign nature of the illness once the diagnosis is confirmed. Treatment of PPMA

Trials with amantadine, high-dose steroids, human growth hormone, pyridostigmine[54] , modafanil[55] and bromocriptine all have been disappointing. In a study of subcutaneous insulinlike growth factor-1 in 22 patients with PPMA, patients had enhanced recovery after fatiguing exercise. However, the treatment had no impact upon strength or exercise-induced fatigue. Intravenous immunoglobulin probably has no beneficial effect on activity limitations but may have modest beneficial effect on muscle strength and pain.[56] One trial with weak methods found that lamotrigine might be effective in reducing pain and fatigue, resulting in fewer activity limitations. Data from 2 single trials suggest that muscle strengthening of thumb muscles (very lowquality evidence) and static magnetic fields (moderate-quality evidence) are beneficial for improving muscle strength and pain, respectively, with unknown effects on activity limitations. These interventions, however, need further investigation. Screening and treating patients for osteopenia or osteoporosis may be appropriate.

Treatment of multifocal motor neuropathy o IV immunoglobulins are effective and commonly used for treating patients with multifocal motor neuropathy. o Either high-dose cyclophosphamide or monthly plasma exchange followed by pulse IV cyclophosphamide has been found effective in patients who do not respond to IV immunoglobulins. These patients do not respond to prednisone or plasmapheresis alone. o Whether the presence of anti-GM1 antibody or its titer has any bearing on the response to therapy is controversial. Inclusion body myositis does not respond well to immunosuppressive medication. Immunosuppressive treatment with corticosteroids may benefit focal myositis and sarcoid myopathy.

THE DISEASES THAT CAUSE FOCAL MUSCLE WASTING ARE MOSTLY SELF-LIMITING AND BENIGN. THEY DO NOT AFFECT THE LIFESPAN OF THE INDIVIDUAL.