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Subject 101: Amyotrophic Lateral Sclerosis: a good reason to get wet?

Amyotrophic Lateral Sclerosis: a good reason to get wet?

Ice bucket challange

Amyotrophic Lateral Sclerosis (ALS) gained a lot of attention during the summer of 2014 due to the social media hype the “Ice Bucket Challenge”. In this challenge people were encouraged to splash a bucket of ice-cold water on their head to raise money for ALS research. This Subject 101 will briefly cover the current state of knowledge about ALS etiology, symptomatology, treatment options and the focus of current research.

Pathophysiology

Amyotrophic Lateral Sclerosis is derived from the observed muscle atrophy (amyotrophy) and the observation of pathological lateral sclerosis in the corticospinal tract.1 ALS is characterized by degeneration and death of both upper and lower motor neurons.
The underlying etiologic mechanisms seem multifactorial, both molecular and genetic, and are still not completely understood.2,3 A multiple hit model causing the malfunction of multiple cellular pathways could be an explanation for the heterogeneity of ALS manifestation.3 Two recent theories attempt to explain the spreading of the disease. In the first theory, a misfolded TDP-43 protein, which is found in almost all ALS patients, causes transcriptional defects, generates oxidative radicals
and inhibits proteasomes. The misfolded proteins might spread to other cells in a prion-like way.3 In the second theory, alteration of TDP-43 concentration reactivates inherited retroviral genes and causes neurodegeneration.3

Symptomatology

The mean age of onset is 58-63 year. The population-based lifetime risk of ALS is 1:350 and 1:400 for men and women respectively.4 ALS is inherited in a Mendelian pattern in 5-10% of the cases.2 Any voluntary muscle can be affected in ALS. The clinical manifestation is therefore heterogeneous.3 Asymmetric upper or lower limb weakness is the most common initial symptom present in 70% of the ALS patients.2 Upper limb weakness often includes hand weakness. In many cases this is associated with the “split-hand syndrome”: weakness and atrophy of the lateral thenar muscles. The medial muscles are often relatively spared.5 This phenomenon results in a decreased manual dexterity. Patients can experience a foot drop (impaired dorsiflexion of the foot) in the case of lower limb weakness.1 In 25% ALS has a bulbar onset affecting the muscles of the tongue and throat. This results in dysarthria or dysphagia.2 The presence of involuntary muscle contractions (fasciculations) in the tongue are highly specific for ALS. Fasciculations in other parts of the body should, however, be interpreted with care.2 Degeneration of respiratory and trunk muscles is an initial symptom in 5% of the patients.2 Less common patterns of presentation include emotional lability, weight loss, fasciculations in the absence of muscle weakness, cramps and frontal lobe dysfunction.6

Diagnosis

Because of the absence of diagnostic tests, ALS diagnosis is mainly based on the observation of both affected upper and lower motor neurons and progression to other regions.2,3 Nerve conduction studies are indicated for the exclusion of ALS mimicking disorders like demyelinating motor neuropathies: motor nerve conduction is only affected in later stages of ALS and sensory nerve conduction remains unaffected during disease progression. Electromyographical examination can reveal typical signal fibrillations in the case of affected lower motor neurons in clinical still unaffected muscles.7

Prognosis and therapy options

Average survival after initial presentation is 2 to 4 years.8 The main cause of death is respiratory failure due to the degeneration of trunk and respiratory muscles.9
The main aim of ALS management is multidisciplinary symptomatic care. This includes non-invasive ventilation to prevent nocturnal hypoxia and prevention of malnutrition.8
Riluzole is the only agent that has any impact on survival. It delays neurodegeneration by inhibition of the excessive activation of the NMDA-receptor
by glutamate (excitatory CNS neurotransmitter).10

Experimental therapies

Multiple drugs showed promising results in preclinical research settings but failed to be effective in clinical trials. The agents that are currently in trial focus on reparation of damaged proteins, the stimulation of affected motor neurons by neurothropic factors (e.g. IGF-I), the stimulation of angiogenesis by VEGF, the  downregulation of mutant genes and the activation of skeletal muscle troponin to regain muscle strength. This mostly concerns preclinical research.10 Future disease modifying agents might give a different response in different ALS subtypes. The identification of the different ALS subtypes is therefore necessary to initiate targeted treatments.3

Conclusion

ALS is a heterogeneous disease resulting in a rapid decline of function and eventually death. It is difficult to diagnose due to the heterogeneous presentation and the absence of diagnostic tests. Currently, there is still no curative agent available. With the progression of (clinical) research and the increased positive attention for ALS curative therapies will hopefully be found in the near future. Until that moment people still have a solid reason to challenge people to get wet.

R.K. Feenstra & M. van Oijen

References

  1. UKuks JBM, Snoek JW. Aandoeningen van de voorhoorncellen, zenuwwortels en perifere zenuwen. In: Klinische Neurologie. ; 2012:188.
  2. Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. Lancet. 2011;377:942-955.
  3. van Es MA, Hardiman O, Chio A, et al. Amyotrophic lateral sclerosis. Lancet. 2017;390(10107):2084-2098.
  4. Logroscino G, Traynor BJ, Hardiman O, et al. Incidence of Amyotrophic Lateral Sclerosis in Europe. J Neurol Neurosurg Psychiatry. 2010;81(4):385-390.
  5. Nalabothu M, Monigari N, Vellalacheruvu N, Elagandula J. Amyotrophic lateral sclerosis presenting as typical split hand syndrome. BMJ Case Rep. 2014.
  6. Ferguson TA, Elman LB. Clinical presentation and diagnosis of Amyotrophic Lateral Sclerosis. NeuroRehabilitation. 2007;22:409-416.
  7. Eisen A, Swash M. Clinical neurophysiology of ALS. Clin Neurophysiol. 2001;112(12):2190-2201.
  8. Hobson EV, McDermott CJ. Supportive and symptomatic management of amyotrophic lateral sclerosis. Nat Rev Neurol. 2016;12(9):526-538.
  9. Andersen PM, Borasio GD, Dengler R, et al. Good practice in the management of amyotrophic lateral sclerosis: Clinical guidelines. An evidence-based review with good practice points. EALSC Working Group. Amyotroph Lateral Scler. 2007;8(4):195-213.
  10. Choudry RB, Galvez-Jimenez N, Cudkowicz ME. Disease modifying treatment of amyotrophic lateral sclerosis. In: UpToDate. ; 2018:1-10.

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