Case History

A 56-year-old man presented with progressive weakness in his legs and hands and slurred speech over the past few months. On examination, the patient had dysarthria, and fasciculations were seen in deltoid muscles on both sides and tongue. There was preferential wasting of the thenar and first dorsal interosseous muscles with relative sparing of hypothenar muscles (“split hand”). There was mild atrophy of the tongue. Muscle strength was 3/5 in distal leg muscles and 2/5 in distal hand muscles. There were no sensory deficits. He had diffuse hyperreflexia, bilateral ankle clonus, jaw jerk, and positive Hoffmann’s reflex in both hands.

Diagnosis: Amyotrophic Lateral Sclerosis

Images 10.8A and 10.8B: Axial and sagittal FLAIR images demonstrate hyperintensity throughout the corticospinal tract (yellow arrows). The corticospinal tract is seen in the posterior limb of the internal capsule on the axial image.

Introduction

  Amyotrophic lateral sclerosis (ALS) is an adult-onset, progressive disorder characterized by degeneration of upper and lower motor neurons.

  It has an annual incidence of 1 to 3:100,000. Most cases are sporadic, with about 5% to 10% being familial. About 20% of familial ALS (FALS) are associated with mutations in the gene that codes for the protein Cu/Zn superoxide dismutase 1 (SOD 1) located on chromosome 21. About two-thirds of familial cases can be attributed to genetic mutations in C9ORF72, SOD1, TARDBP, or FUS.

  Males are affected more frequently than females.

  Juvenile ALS is more frequently familial in nature than the adult-onset forms. Mutations in the alsin (ALS2), senataxin (SETX), and spatacsin (SPG11) have been associated with FALS with juvenile onset and slow progression. However, SOD1 and FUS mutations can lead to juvenile-onset malignant forms of ALS and should be screened in ALS patients with an earlier age of onset and an aggressive progression, even if there is no apparent family history.

Clinical Presentation

  Most patients present with asymmetric weakness in the distal extremities. About 20% present with bulbar symptoms—dysarthria, dysphonia, dysphagia, or difficulty breathing.

  Later symptoms include constipation, early satiety, bloating with delayed gastric emptying, urinary urgency without incontinence, and weight loss. Patients may also display executive dysfunction, subjective sensory symptoms (ie, tingling), or parkinsonism. Pseudobulbar palsy, a condition of “emotional incontinence” in which patients laugh or cry without experiencing the underlying emotion, is a common symptom.

ALS, amyotrophic lateral sclerosis; LMN, lower motor neuron; UMN, upper motor neuron.

Radiographic Appearance and Diagnosis

  Hyperintensity of the corticospinal tract may be seen on T2-weighted images throughout its course in the brain, brainstem, and spinal cord. The appearance of the corticospinal tract in the spinal cord is called the “snake-eye” sign due to its resemblance to a pair of dice, each rolled to one.

  Cortical iron deposition may be seen on susceptibility-weighted imaging.

  PET studies have shown diffuse gliosis in white matter tracts due to loss of inhibitory cortical interneurons in the motor cortex.

  The diagnosis can be confirmed with an electromyography (EMG), which shows fibrillation and fasciculation potentials. The motor units may be polyphasic with increased amplitude and long duration. With chronic denervation there are large motor unit potentials.

  The El Escorial criteria (EEC) for the diagnosis of ALS requires:

        A criteria:

        A1: evidence of LMN degeneration by clinical, electrophysiological, or neuropathological examination

        A2: evidence of UMN degeneration by clinical examination

        A3: progressive dissemination beyond typical nerve supply areas

        B criteria:

        B1: electrophysiological and pathological evidence of other disease processes that might explain the signs of LMN and/or UMN degeneration, and

        B2: neuroimaging evidence of other disease processes that may explain the clinical symptoms

The EEC defines four body regions to be evaluated:

       1.  Brainstem (bulbar)

       2.  Cervical (neck and upper extremities)

       3.  Thoracic (trunk, abdominal wall)

       4.  Lumbosacral (lumbar spine and lower extremities)

  Diagnostic categories

          Clinically definite ALS is defined on clinical evidence alone by the presence of UMN, as well as LMN signs, in three regions.

          Clinically probable ALS is defined on clinical evidence alone by UMN and LMN signs in at least two regions with some UMN signs necessarily rostral to (above) the LMN signs.

          Clinically probable–laboratory-supported ALS is defined when clinical signs of UMN and LMN dysfunction are in only one region, or when UMN signs alone are present in one region, and LMN signs defined by EMG criteria are present in at least two limbs, with proper application of neuroimaging and clinical laboratory protocols to exclude other causes.

Image 10.8C: Axial FLAIR images demonstrate hyperintensity in the corticospinal tracts in the primary motor cortex of the frontal lobe can be seen as a subtle hyperintensity. Image 10.8D: Axial FLAIR image demonstrates the corticospinal tract in the posterior limb of the internal capsule. Image 10.8E: Axial FLAIR image demonstrates the corticospinal tract in the cerebral peduncle. Image 10.8F: Axial T2-weighted image demonstrates the corticospinal tract in the pons. Image 10.8G: Axial T2-weighted image demonstrates the corticospinal tract in the upper medulla. Image 10.8H: Axial T2-weighted image demonstrates corticospinal tract in the lower medulla, at the level of the pyramids where the corticospinal tract decussates. Image 10.8I: Axial T2-weighted image demonstrates now crossed corticospinal tract in the upper cervical cord. The appearance there is known as the “snake-eye” sign. In all images the red arrow points to the corticospinal tract.

          Clinically possible ALS is defined when clinical signs of UMN and LMN dysfunction are found together in only one region or UMN signs are found alone in two or more regions; or LMN signs are found rostral to UMN signs and the diagnosis of clinically probable–laboratory-supported ALS cannot be proven by evidence on clinical grounds in conjunction with electrodiagnostic, neurophysiologic, neuroimaging, or clinical laboratory studies. Other diagnoses must have been excluded to accept a diagnosis of clinically possible ALS.

Image 10.8J: Wallerian degeneration of lateral fasciculi (red arrow) of spinal cord in a patient with ALS-FTD-complex. The dorsal, sensory nerve root (blue arrow) is preserved, while the anterior, motor nerve root is significantly atrophied.

Source: Luty AA, Kwok JB, Thompson EM, et al. Pedigree with frontotemporal lobar degeneration—motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9. BMC Neurol. 2008;8:32.

Treatment

  Riluzole, a glutamate antagonist, is the only Food and Drug Administration (FDA) approved drug for the treatment of ALS. It prolongs survival by 3 to 6 months. Physical and occupational therapy is essential to maintain the patient’s mobility and daily function for as long as possible.

  ALS is a progressive disease. The median survival from the time of diagnosis is 3 to 5 years, and neuromuscular respiratory failure is the most common cause of death. However, approximately 10% of ALS patients can live for 10 years or more after diagnosis.

References

1.  Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. Lancet. March 2011;377(9769):942–955.

2.  Chiò A, Pagani M, Agosta F, Calvo A, Cistaro A, Filippi M. Neuroimaging in amyotrophic lateral sclerosis: insights into structural and functional changes. Lancet Neurol. December 2014;13(12):1228–1240.

3.  Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009;73:1227–1233.

4.  Luty AA, Kwok JB, Thompson EM, et al. Pedigree with frontotemporal lobar degeneration—motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9. BMC Neurol. 2008;8:32.