Are all motor neurons effective?

Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis is a degenerative disease of the 1st and 2nd motor neurons. The disease usually manifests itself in the 6th – 8th centuries. Decade of life and often begins with atrophic paresis of the small hand muscles or other muscle groups (shoulder, calves). As the disease progresses, it spreads to other muscles, with the picture of flaccid atrophic (2nd motor neuron damaged) mixed with spastic paresis (1st motor neuron damaged). If the caudal cranial nerves are affected, bulbar symptoms with swallowing and speech disorders occur. Fasciculations of the muscles and fibrillation of the tongue also occur. Sensitivity disorders are not a typical symptom of the disease, but occur in some of the patients over time. There is no curative therapy; however, numerous symptomatic therapy options can extend survival time and improve quality of life. Patients usually die of respiratory failure 2–5 years after the onset of the disease.

Epidemiology

  • Incidence: 2–3 cases / 100,000 population per year
  • Gender: ♂> ♀
  • Age: Most frequent onset of the disease between the 6th and 8th decade of life, in familial form around the age of 50
  • Distribution: Sporadic, familial and endemic forms

Unless otherwise stated, the epidemiological data refer to Germany.

etiology

  • About 90-95% of cases are sporadic (sporadic ALS, SALS)
    • Cause not known, multifactorial origin likely
  • With approx. 5–10% familial accumulation (familial ALS, FALS)
    • Requirement: min. two family members affected
    • Gene mutations
      • C9orf72 gene (in 25-30% of all FALS cases in Europe)
        • Clinical features: Faster course of the disease, more frequent onset with bulbar symptoms and an overlap with frontotemporal dementia (ALS / FTD) than with the other forms of ALS
      • Copper-zinc superoxide dismutase gene (SOD1) (in 10-20% of FALS cases in Europe, 3% of sporadic cases)
      • FUS gene (in 4–6% of FALS cases, rarely also in sporadic ALS)
      • TDP-43 gene (in 4–8% of FALS cases, also rarely occurring in sporadic ALS)
    • Inheritance: Mainly autosomal dominant inheritance, sometimes with incomplete penetrance
      • Usually monogenic inheritance
  • Endemic form: As Western Pacific ALS (ALS PD complex) in combination with dementia and Parkinson's syndrome on islands in the Western Pacific
    • The cause of the endemic occurrence is unknown, a triggering environmental factor has not yet been identified
    • The prevalence in the affected areas increased by a factor of 50–100, but has declined over the past decades

Symptoms / clinic

Full screen of the ALS

Initial symptoms

  • Progressive paresis and muscular atrophy
  • Fibrillation of the tongue and fasciculations
  • Painful muscle cramps ("crampi")
  • Speech and swallowing disorders
  • Sensitivity disorders (not a primary symptom, but not an exclusion criterion!)

The symptoms are often mild and unspecific at the beginning. The diagnosis is therefore often delayed and made after numerous visits to the doctor!

Symptoms in the course

Fasciculations are not pathognomonic for ALS! They can also occur with other diseases, as an undesirable drug effect or especially as benign fasciculations without disease value!

Gradient and special forms

Amyotrophic lateral sclerosis is a heterogeneous disease, the spectrum of which includes not only "classic ALS", numerous phenotypic variants and forms. Diseases such as primary lateral sclerosis (clinically only signs of degeneration of the 1st motor neuron) and progressive spinal muscular atrophy (clinically only signs of degeneration of the 2nd motor neuron) have long been regarded as separate disease entities. The possible transition to a classic ALS with clinical signs of the 1st and 2nd motor neurons as well as pathological and molecular genetic findings suggest that there are different manifestations of a pathological process. This can also lead to non-motor deficits such as cognitive impairment. The subdivision presented below is nevertheless of clinical relevance, especially with regard to the variable prognosis.

Progressive Bulbar Paralysis (PBP)

Amyotrophic lateral sclerosis with frontotemporal dementia (ALS-FTD)

  • Definition: Motor symptoms of amyotrophic lateral sclerosis and behavior or speech abnormalities that meet the diagnostic criteria for frontotemporal dementia (FTD) (about 5% of ALS patients). Mild, cognitive impairments are much more common in ALS.
  • Possible symptoms
    • Aggressiveness, disinhibition
    • Apathy or passivity, social withdrawal
    • Affect flattening, loss of empathy
    • eating disorder
    • Persevered, stereotypical, or compulsive behavior
  • Additional diagnostics
    • Neuropsychological testing (ECAS, CERAD test battery, Frontal Systems Behavior Scale)
    • If necessary, CSF diagnostics as part of dementia diagnostics
    • Imaging if necessary
      • MRI or CT of the head: Frontal and / or anterior temporal atrophy possible
      • PET or SPECT: frontal hypoperfusion or frontal hypometabolism
  • Prognosis: Associated with a faster course of ALS
  • therapy

Primary Lateral Sclerosis (PLS)

  • Definition: Clinically only signs of degeneration of the 1st motor neuron
  • Symptoms / clinic
  • Additional diagnostics: EMG to rule out subclinical denervation as a sign of damage to the 2nd motor neuron
  • Therapy: Symptomatic (myotonolytics such as baclofen, physiotherapy)
  • forecast
    • Slower progression and longer survival than ALS
    • If signs of damage to the 2nd motor neuron appear (often), the ALS diagnosis can be made (see Treatment of ALS)

Progressive Spinal Muscular Atrophy (PMA)

  • Definition: Clinically only signs of degeneration of the 2nd motor neuron
  • Symptoms / clinic
  • Diagnostics: Clinical and electrophysiological evidence (EMG) of the degeneration of the 2nd motor neuron in at least two regions
    • Often subclinical involvement of the 1st motor neuron
  • Differential diagnoses: Hereditary diseases of the lower motor neuron, motor neuropathies, myopathies and diseases of the muscular endplate
  • forecast
    • Median survival time around four years, along with longer courses
    • Transition to classic ALS possible (20–30% of cases), then treatment of ALS

Diagnosis

Diagnostic principles

  • Clinical evidence of damage to the 1st and 2nd motor neurons within different body regions and progression of the findings
  • Electrophysiological diagnostics to confirm clinical findings (EMG) and to rule out differential diagnoses (ENG)
  • Further diagnosis of exclusion, depending on the symptoms

Diagnostic criteria for ALS are summarized in the El Escorial criteria. The current revised El Escorial criteria are currently being revised because they are not compatible with the earliest possible diagnosis of ALS and some of the symptoms mentioned as exclusion criteria (sensory disorder, sphincter disorder and dementia) can certainly occur with ALS. According to the guideline, they are not recommended for use in clinical practice.

Clinical-neurological examination

Basic diagnostics

  • EMG: Confirmation of the clinical diagnosis and possibly evidence of denervation in the absence of clinical signs of damage to the 2nd motor neuron
    • Neurogenic damage pattern: Pathological spontaneous activity (positive sharp waves, fibrillations) and large-amplitude, but lightened activity pattern (so-called giant potentials)
  • ENG: Exclusion of conduction blocks in motor neurography
  • MRI
    • Spinal MRI: diagnosis of exclusion (e.g. compressive myelopathy due to cervical spinal stenosis, polysegmental radiculopathy)
    • Cranial MRI: diagnosis of exclusion
    • Changes in the course of the pyramidal trajectory are unspecific and do not serve as a diagnostic criterion for ALS
  • Laboratory diagnostics (blood)
    • No ALS-specific laboratory marker, possibly CK ↑
    • Basic diagnostics (guideline recommendation): ESR, CRP, blood count, ALAT / ASAT, fT3, fT4, TSH, vitamin B12, Serum electrophoresis, immunoelectrophoresis, CK, creatinine, electrolytes, glucose
    • Extended laboratory diagnostics (depending on differential diagnoses)
  • CSF diagnostics
    • Indication: For differential diagnosis especially of inflammatory diseases
    • Slight increase in total protein possible
  • Pulmonary function test and blood gas analysis
  • Weight measurement
    • Follow-up of the catabolism associated with the disease
  • Neuropsychological testing
    • Edinburgh Cognitive and Behavioral ALS Screen (ECAS)
      • Screening test for cognitive and behavioral disorders in ALS patients
      • Average duration 25 min
      • In the event of deficits, additional testing by a clinical neuropsychologist is recommended

Advanced diagnostics

  • Muscle biopsy
  • Genetic diagnostics: If the presence of familial ALS is suspected
    • indication
      • In young patients (
      • For differential diagnostic exclusion of Kennedy syndrome (androgen receptors)
    • Implementation: Genetic testing is carried out in the order of decreasing frequency of the individual mutations
    • Legal aspects: Advice according to the Genetic Diagnostics Act as well as written consent mandatory
      • Predictive diagnosis of clinically unaffected family members (siblings and children of the index patient) only after presentation to a specialist in human genetics

There are currently no preventive or therapeutic consequences from genetic testing!

pathology

Macroscopic: atrophy of the entire motor system, e.g. narrowing of the gray matter due to atrophy of the anterior roots