At a Glance

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized neuropathologically by a loss of upper motor neurons in the motor cortex and lower motor neurons in the anterior horn of the spinal cord. Clinically, ALS should be suspected in patients that present with painless focal muscle weakness and atrophy that progresses over time and spreads through the body following neuroanatomical continuities.

The site of onset is variable and can typically be in the legs, arms, or oropharynx (so called bulbar onset). The limb onset is characteristically asymmetrical. Patients, whose weakness begins in the respiratory nerves (innervating the intercostal muscles and the diaphragm), causing shortness of breath and fatigue as the initial symptom, are much more difficult to identify. Frequent, albeit unspecific, symptoms are weight loss and muscle cramps.

Patients with a predominant involvement of the upper motor neuron present with spasticity that can cause pain, a symptom otherwise typically absent from the clinical picture of ALS. The clinical course is invariably progressive, and, therefore, even in ambiguous cases, the diagnosis becomes clear over time. Deviations from the expected progressive course of the disease, such as stabilization of symptoms or significant clinical improvements, should raise questions about the initial diagnosis and warrant careful reexamination of the patient.

Continue Reading

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

ALS remains a clinical diagnosis. However, a range of laboratory tests are needed to allow early diagnosis and to rule out other potentially more treatable differential diagnoses (Table 1).

Genetic testing is only advisable in the minority of patients who have a positive family history for motor neuron disease. In presymptomatic genetic diagnosis, testing needs to be preceded and accompanied by qualified genetic counseling.

Table 1
electromyography/pathologic spontaneous activity, acute and chronic denervation transcranial magnetic stimulation/increased central conduction time genetic testing: SOD1 – TDP43 – FUS mutations

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Since the diagnosis of ALS does not depend on positive lab results, the risk for confounding factors is very limited.

It should be noted that the only FDA approved drug to treat ALS, riluzole, often causes an increase in liver transaminases (GOT(AST)/GPT(ALT).

ALS is associated with increased creatine kinase (CK). However, this association is nonspecific and, therefore, not diagnostic. The causes for asymptomatic hyper-CK-emia are manifold and range from statin use to exercise.

What Lab Results Are Absolutely Confirmatory?

The most important test for confirming the diagnosis of ALS is electromyography to show acute and chronic denervation as a sign of lower motor neuron involvement. Upper motor neuron involvement can be tested by transcranial stimulation of the motor cortex.

Electroneurography is useful to diagnose nerve conduction blocks when only the lower motor neuron is affected.

Magnetic resonance imaging (MRI) can detect changes in the pyramidal tract and the motor cortex. However, this is only of limited diagnostic value, but it can be used to track disease progression.

A range of laboratory tests complement the electrophysiological and imaging work-up and help assure an early diagnosis of the condition. The basic laboratory work up includes ESR, CRP, RBC and WBC, blood glucose, GOT, GPT, TSH, T3 and T4, vitamin B12 (methylmalonic acid, homocysteine), E’lytes (Na, K, Ca, Cl, PO4), CK, creatinine, as well as protein- and immune-electrophoresis. Vital capacity and blood gas analysis are important for assessing the prognostically important extent of the respiratory function in ALS patients.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Although the clinical diagnosis of ALS is typically straight forward, it is important to rule out effectively treatable diagnoses.

A normal cerebrospinal fluid (CSF) can rule out chronic radiculopathy. CSF protein and Tau can be increased in ALS, especially in particularly aggressive forms.”

A muscle biopsy can identify the rare cases of inclusion body myositis that can mimic ALS.

GM-1 antibodies in the serum indicate multifocal motor neuronopathy.

Male patients with only lower motor neuron involvement and androgen insensitivity signs (i.e., gynecomastia, reduced fertility, testicular atrophy) with or without a family history need tested for CAG repeat expansion in their androgen receptor gene to rule out X-linked spinal and bulbar muscular atrophy (also called Kennedy disease).

A special challenge is the diagnosis of paraneoplastic syndromes that presents as motor neuron disease. This can be suspected when additional neurological symptoms are present, such as cerebellar symptoms, seizures, or sensory deficits. Detection of anti-Hu antibodies should prompt the search for prostate cancer and small cell lung cancer. In women with predominant symptoms of the upper motor neuron, sometimes breast cancer can be detected. Paraproteinemias or indication of lymphoproliferative disease should prompt follow-up with a bone marrow biopsy.