ALS

Classical MNDs

Amyotrophic Lateral Sclerosis (ALS) – originally described by Charcot and thus it is often called Charcot's disease in Europe. Classical ALS is a distinct syndrome characterized by a combination of UMN and LMN signs and symptoms without other neurological problems and no other explanation but a motor system disorder. In approximately two thirds of patients with ALS, the disease takes this form.

Progressive Muscular Atrophy (PMA) – constitutes roughly 8 to 10 percent of patients with sporadic ALS. PMA is sometimes called Aran-Duchenne type of motor neuron disease (MND). The initial symptoms are manifestations of LMN involvement of the spinal cord and, in a later stage, of the lower brainstem. If UMN signs do not develop within two years, the disease is likely to remain PMA.

Primary Lateral Sclerosis (PLS) – was first described by Erb in 1875. The clinical signs of PLS consist only of UMN signs. It is the most rare of all the forms of ALS.

Other diseases that mimic ALS

When we deal with the potential diagnosis of ALS, it is essential to exclude treatable diseases and other less severe MNDs, although they are very rare. A good motto is: Leave no stone unturned! If a person has motor neuron damage, there are certain findings which clearly suggest another diagnosis or an additional problem besides a MND. These findings include: sensation problems, significant bladder problems, or peripheral nervous system problems.

Polyradiculopathy/myelopathy
A combination of chronic cervical and lumbosacral polyradiculopathy (pinching of the nerves as they exit the cervical and lumbar spine) and spondylitic myelopathy (bony overgrowth in the spine that pinches the spinal cord) can cause a variety of upper and lower motor neuron signs without sensory symptoms and can closely resemble ALS.

Post-polio Syndrome
Post-poliomyelitic muscular atrophy is characterized by progressive muscle atrophy and weakness that develops at least fifteen years after recovery from acute polio. It usually affects the muscles previously affected by polio and looks like a LMN disorder. In general it does not cause UMN signs.

Motor Neuropathy with Anti-GM1 Antibody
Motor neuropathy with high anti-ganglioside antibodies1 is manifested as predominantly lower motor neuron disease with multifocal conduction block on EMG-NCV studies. Conduction block are areas along the motor nerves where the electric potential is not carried as well (i.e. blocked) resulting in a decrease in the amount of response detected over the muscle. This condition is potentially treatable with immune system modulating drugs.

1An antibody is a protein made by the immune system. This protein is designed to attach to and help destroy a particular "antigen". Antigens are proteins or parts of proteins that are usually foreign. In autoimmune diseases, the antigen is not foreign but rather part of your body; the result of which is your immune system attacking your own body. In this case the antigen is the ganglioside on the motor nerve and the covering to the nerve that is being attacked by the immune system.

MND and Gammopathy/paraproteinemia
Monoclonal gammopathy (an excess of a single immune system protein) is more frequently found in patients with ALS than in the general population of similar age groups. IgM paraproteinemia also is reported in rare cases of motor neuron disease of predominantly LMN. Evidence that some patients with ALS have monoclonal gammopathy, positive anti-GM1 antibody, or both led to a hypothesis that ALS is an unconventional autoimmune disease.

Heavy Metal Intoxication
Lead intoxication may cause motor neuropathy, whereas chronic mercury intoxication is reported to produce upper and lower motor neuron signs along with other CNS manifestations.

Hexosaminidase-A Deficiency
Adult hexosaminidase-A deficiency (an enzyme deficiency responsible for Tay Sachs Disease) is associated with nervous system problems. It can causes pure LMN disease, which mimics spinal muscular atrophy, or both LMN and UMN with a resemblance to ALS. In this rare condition there are almost always other neurological findings in addition to the damage to the motor system.

When there are UMN signs, either alone or with LMN signs; spine disease, hyperparathyroidism, hyperthyroidism, adrenoleukodystrophy, mitochondrial disease, and spastic paraparesis should be ruled out. Furthermore, Lyme disease, vasculitis, and certain multi-system diseases should be investigated as they can include motor nerve involvement and mimic ALS.

Differential Diagnosis

Pure LMN

  • Spinal Muscular Atrophy
  • Progressive Muscular Atrophy
  • Inflammatory Neuropathies
    • CIDP
    • Multifocal Conduction Block
  • Motor Neuropathies
    • Associated with tumors
    • Associated with metabolic problems
      • porphyria
      • gangliosidoses (including Tay Sachs variants)
    • Associated with toxins
      • lead
    • Associated with immune system abnormalities
      • monoclonal gammopathies and myeloma
    • Associated with vasculitis
  • Electrical Injuries
  • Viral Infections
    • Polio
    • HIV

Pure UMN

  • Primary Lateral Sclerosis
  • Familial Spastic Paraparesis
  • Carrier of Adrenoleukodystrophy
  • Multiple Sclerosis
  • Mitochondrial Diseases
  • CNS vasculitis
  • Leukodystrophies
  • Vitamin E Deficiency (Usually with sensory)
  • B12 Deficiency (usually with sensory)

UMN and LMN

  • Amyotrophic Lateral Sclerosis
  • Spine disease
  • Vasculitis
  • Mitochondrial disease
  • Lyme Disease
  • Endocrine Dysfunction
  • Thyroid or Parathyroid disease

 

Diagnosing ALS

What is the clinical picture of ALS?

ALS is a MND characterized by damage to both the UMN and the LMN. ALS generally affects people between 55 and 75 years of age although all ages can be involved. The prevalence (how many people have the disease at one time) rate is about 4 per 100,000 while the incidence (how many new cases occur in a time period) is about 1 per 100,000 new cases each year. There is a male-to-female ratio of about 2:1.

The symptoms of ALS vary from one person to the next. Symptoms reflect weakness and thinning of muscles due to the involvement of the LMN as well as stiffness from the UMN involvement. Onset can begin in the muscles that are innervated by the bulbar neurons (speaking, swallowing) or in muscles innervated by nerve cells in the spinal cord causing weakness in one arm or one leg. A person newly diagnosed with ALS may trip, drop things, slur their speech, twitch, and laugh or cry uncontrollably. The person may also experience abnormal fatigue of the arms or legs and muscle cramps. Walking and activities requiring the hands may prove more difficult for a person with the disease. In 20% of ALS cases, speech and swallowing begin to decline first. Another 40% have symptoms in the arm first while the rest of people experience problems due to leg involvement. Over time the disease spreads from one area to another and gradually the people living with ALS will lose movement in muscles throughout the body, including the muscles of breathing. While the average lifespan is about 36 months, it is important to recognize that 20% of people live for five years and 10% of patients live for 10 years.

There are some restricted variants of the illness in which there is no spread outside of the initial area of involvement. These restricted variants include Bulbar palsy in which speech and swallowing are involved and some focal amyotrophies in which only one extremity is involved with either little or no progression.

How is the diagnosis of ALS made?

The diagnosis is made by identifying damage to only the motor system, with damage to both the upper and lower motor neurons.2 In addition, all other possible causes of that damage must be excluded and there must be progression of the weakness over time with involvement of multiple areas in the nervous system. The areas that are evaluated include the bulbar region (speech and swallowing), cervical region (arms, diaphragm), thoracic region (muscles of breathing), and the lumbar region (legs).

2An extended discussion of the motor system and the signs and symptoms indicating damage to it can be found above in the sections entitled: What is the Motor system? and How can_we tell Motor Neuron damage?

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