Objective Diagnosis of Upper Motor Neuron Disease

Abstract & Commentary

Source: Chan S, et al. Amyotrophic lateral sclerosis and primary lateral sclerosis: Evidence-based diagnostic evaluation of the upper motor neuron. Neuroimaging Clin N Am. 2003; 13:307-326.

Amyotrophic lateral sclerosis (ALS) is a clinical diagnosis made with a high degree of accuracy (> 90%) by physicians familiar with the disease. No test is diagnostic for ALS. Electromyography provides objective evidence of lower motor neuron involvement while blood tests and nerve conduction studies are used to exclude mimics. Upper motor neuron involvement in ALS is presently demonstrated by clinical examination. Primary lateral sclerosis (PLS), the purely upper motor neuron variant of ALS, has a calculated incidence of 1/107, or 0.5% that of ALS. It excludes other disorders including cervical spondylosis, multiple sclerosis, or spinal cord compression from tumor. Needle EMG and blood studies are normal, and again the presence of upper motor neuron disease is based on examination. Objective diagnosis of upper motor neuron disease would facilitate diagnosis. Early confirmatory diagnosis of ALS and PLS would permit rapid enrollment of such patients into therapeutic clinical trials before irreversible degeneration of motor nerves occurred. Advanced imaging techniques may provide this critical step.

Using evidence-based analysis of the literature culled from a MEDLINE PubMed review from 1966 to June 2002, the following conclusions were drawn. Proton density-weighted magnetic resonance (MR) imaging, using conventional spin-echo or fast spin-echo, can reliably detect upper motor neuron degeneration in the posterior limb of the internal capsule as indicated by signal hyperintensity and is recommended in the evaluation of patients with suspected motor neuron disease. FLAIR images, which may also detect corticospinal tract abnormalities in the brain, must be interpreted with caution, as these findings are seen in the normal population. Decreased T2 signal in the precentral gyrus is not a reliable imaging sign and is unlikely to be helpful with the exception of the younger than 50-year-old patient with no previous neurologic history. Enlargement of the central sulcus, atrophy of the precentral gyrus, corpus callosum atrophy, and signal abnormality are similarly of questionable reliability at this time. Hyperintensity in the spinal cord can be appreciated using T2-weighted axial views of the cervical cord. It remains unclear as to which pulse sequence is best to use. Diffusion tensor and magnetization transfer imaging are newer MR imaging techniques. The evaluation of the corticospinal tract remains to be established.

MR spectroscopy (MRS) findings indicate that N-acetylaspartate (NAA) is decreased in the motor cortex in PLS compared to normals. This imaging modality can help identify upper motor neuron degeneration. Both single and multivoxel MRS appear useful for such evaluation. However, before these methodologic data are used as neuronal markers in clinical trials, high test-retest reliability must be demonstrated, and standardization of methods will be needed.

Absent a contraindication to MR imaging, head computed tomography (CT) and CT-myelography no longer play a role in the work-up of a patient with suspected ALS. Newer techniques, including single photon emission computed tomography (SPECT), resting positron emission tomography (PET), activation PET, and functional MRI (fMRI), presently have no role in the evaluation of patients with suspected motor neuron disease. Further research is warranted and necessary in these areas.

Commentary

ALS is an age-dependent disorder affecting approximately 1.5/100,00 individuals. It exists in several forms: classic sporadic ALS (Lou Gehrig’s or Charcot’s disease) and familial ALS most often associated with mutations of the superoxide dismutase (SOD1) gene. The Western Pacific form is often associated with dementia and known as the ALS-dementia complex of Guam.

For unclear reasons, perhaps environmental, ALS incidence rates are increasing more rapidly than may be explained by an increasingly aging population.1 Two recent reports support an environmental trigger among Gulf War veterans. Among 2.5 million military personnel serving over a 10-year period beginning in August 1990, there were 107 confirmed cases of ALS, an occurrence rate of 0.43/100,000. Those deployed to the Gulf region during the war period demonstrated a twofold greater risk.2 Among veterans younger than 45, an excess incidence was also observed, again suggesting a war-related environmental trigger.3 War veterans were exposed to numerous environmental toxins including organophosphate pesticides, multiple immunizations, and heavy metals from exploded armaments. Much work remains to tease the chaff from the kernel. —Michael Rubin, MD, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, Assistant Editor, Neurology Alert.

References

1. Turner B, et al. Amyotroph Lateral Scler Other Motor Neuron Disord. 2003;4:1.

2. Horner RD, et al. Neurology. 2003;61:742-749.

3. Haley RW. Neurology. 2003;61:750-756.