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:
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Thyroid functions
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Rheumatoid factor
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Serum ACE assay
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Serum anti-GM1 antibodies
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Viral studies
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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
A chest radiograph may reveal cervical rib or apical lung lesions or hilar adenopathy
A spine radiograph 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 findings in white North American patients with Hirayama disease include loss of attachment (LOA) on neutral images and forward displacement of the dura with flexion. Findings are often present on neutral MRIs and are better delineated in the flexion MRI. [53]
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. [54]
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. [55]
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.
Other Tests
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 the AR 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.
Procedures
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 [26] (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 [56] 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.
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A man with neuralgic amyotrophy presenting with wasting of deltoids involving the right side more than the left.
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A middle-aged man with (atypical) anterior horn cell disease presenting with wasting of the right quadriceps.
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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.
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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.
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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.
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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.
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Wasting of right forearm and both hand muscles in a patient with Hirayama Disease. Note the oblique atrophy of right forearm.
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Wasting of small muscles of the hands in a patient with Hirayama Disease.
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T2-weighted cervical spine MRI of a patient with Hirayama disease showing focal cord hyperintensity at C5-C6 level.
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T2-weighted cervical spine MRI of the same patient during neck flexion showing anterior displacement of the posterior dural wall with flattening and compression of the cord against the bodies of the vertebrae with prominent dorsal epidural flow voids.
