Amyotrophic lateral sclerosis

Notes

Introduction

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND), a progressive neurodegenerative disease characterised by worsening paralysis, disability and eventually death.

It tends to develop in the mid-to-late 50’s and is seen more commonly in men. Presentations can vary significantly but the onset is commonly with asymmetrical weakness of a limb. The disease is progressive, eventually affecting more muscles groups, including those involved in respiration. Death most commonly results from respiratory failure, with a median survival of 3-5 years after symptom onset.

Though the condition was described independently by a number of clinicians, Jean-Martin Charcot (a French neurologist) is often credited with the first complete description. The term amyotrophic refers to lack of muscle growth, whilst the term lateral sclerosis refers to ‘scarring’ found in the lateral (motor) pathways in the spinal cord.

The terminology can be confusing as it may be used in different ways. At times people will use ALS and MND interchangeably. In the US, ALS may also be referred to as Lou Gehrig’s disease after the famous baseball player who suffered with the condition.

Epidemiology

In the western world there is an incidence of approximately 1-2 cases of ALS per 100,000 people.

The majority of cases, around 90%, are sporadic whilst the remaining 10% are familial. Sporadic disease occurs more commonly in men than in women (almost 2:1) though the gender balance is more even in inherited disease.

Onset is typically in the mid to late 50’s though early onset is seen in familial forms of the disease.

Genetics

The C9orf72 expansion is the most commonly identified mutation in patients with familial ALS.

The genetics of ALS are complicated and our understanding is incomplete. There are a number of mutations that have been identified in those with familial ALS (approximately 10% of cases). The first identified was superoxide dismutase 1 (SOD-1), whilst the most commonly identified is the C9orf72 mutation (discussed briefly below).

C9orf72 is a gene that codes for a protein that is found in numerous tissues, in particular the cerebral cortex and motor neurones. It contains a hexanucleotide repeat, GGGGCC. Mutations of C9orf72 have been associated with ALS and as such a great deal of research has been conducted to characterise this relationship.

It is thought that an excess of the hexanucleotide repeat, GGGGCC can lead to ALS (as well as frontotemporal dementia), typically when the number of repeats exceeds 30. It is the most common genetic cause of ALS.

Research has shown the majority of neurologically well people have less than 11 such repeats. These repeats are read bidirectionally to repetitive RNA which can be translated to dipeptide repeat proteins (DPRs).

A potential common pathway is in the development of inclusions of TAR DNA-binding protein 43, a feature of ALS. Mutations of C9orf72 and DPRs have been shown to be associated with the development of these inclusions. Overall three main mechanisms have been described:

  • Loss of function of C9orf72 protein
  • Gain of function of dipeptide repeat proteins (DPRs)
  • Gain of function from C9orf72 repeat RNA

Each of these leads to motor neurone loss and the development of ALS.

Clinical features

ALS can present in a myriad of ways affecting different parts of the body with upper and/or lower motor neuron signs.

The most common forms of presentation are asymmetrical limb onset (around 80%) followed by bulbar onset (around 20%). Rarer presentations include diaphragmatic onset and more generalised presentations.

Limb onset

The majority of patients, around 80%, present with asymmetrical weakness of a limb.

  • Upper limb onset: hand weakness is commonly the first symptom noted with a loss of dexterity. Wrist drop may be noted.
  • Lower limb onset: foot drop is often the first symptom noticed. Patients may notice difficulties with balance particularly when running.

Bulbar onset

Around a fifth of patients will present with bulbar onset with features of dysarthria and dysphagia. A change in the character of ones voice may be noted. Patients may have difficulty swallowing leading to choking or aspiration.

Cognitive symptoms

There is a strong association between ALS and frontotemporal dementia which affects around 15% of patients. All patients should be screened at presentation and at regular follow-ups for dementia.

A ‘pseudobulbar affect’ may be seen - this describes involuntary laughing and crying. Other mood changes may be seen either in conjunction with frontotemporal dementia or independent of it.

Upper and lower motor neuron features

Findings depend on the site of onset, the mix of UMN and LMN signs and the stage of progression. Generally clinical signs can be divided into either UMN or LMN.

LMN:

  • Weakness
  • Muscle atrophy
  • Hyporeflexia
  • Fasciculations
  • Muscle cramps
  • Dysarthria, dysphagia (tongue and pharyngeal weakness)

UMN:

  • Hypertonia
  • Hyperreflexia
  • Spastic gait
  • Ankle clonus
  • Jaw clenching
  • Exaggerated jaw jerk
  • Dysarthria, dysphagia (due to lack of coordination and spastic dysarthria)

Natural history

The disease is relentlessly progressive, thought the rate varies between individuals. After onset, disease spreads to other muscle groups, at times following a sequential pattern. For example those with unilateral arm onset may then see the contralateral affected followed by the ipsilateral leg, contralateral leg and then bulbar muscles. A similar pattern may be seen in those with unilateral leg onset (first to the contralateral leg etc).

With time bulbar symptoms become more troublesome, with increasing swallowing difficulties impacting nutrition and risking aspiration events. Muscle weakness turns to atrophy and weight loss.

Though a small minority present with onset in the muscles of respiration, in the vast majority this is a feature of disease approaching its end stage following progression from other muscle groups. Respiratory failure is the most common cause of death.

Investigations

Though the diagnosis of ALS remains largely clinical, investigations can be helpful both in ruling out other disease processes as well as providing supportive findings.

Electrophysiology

  • Electromyography: findings consistent with both acute and chronic denervation can be found. Also helps in the identification of fasciculation.
  • Nerve conduction studies: motor conduction can be normal or demonstrate abnormalities that reflect denervated muscles. Sensory conduction is normal

Genetics

May be organised in young patients and those with a family history of MND. The two most commonly identified mutations are C9orf72 and SOD1.

MRI

An MRI brain and spine may be ordered depending on the presentation, site of disease and considered differentials. Though MRI is preferred occasionally CT may be used.

Changes associated with ALS include increased signal on T2-weighted imaging of the corticospinal tracts.

Other

Routine blood tests should be sent along with a blood borne virus screen (HIV, hepatitis B/C), vitamin B12, folate and creatine kinase.

Antibodies may be sent to try to rule out other neurological conditions. These include:

  • Acetylcholine receptor antibodies (to exclude myasthenia gravis)
  • Voltage-gated calcium-channel antibodies (to exclude Lambert-Eaton syndrome)
  • Anti-GM1 antibodies (to evaluate for multifocal mononeuropathy)

Further tests may include lyme serology, muscle biopsy and lumbar puncture.

Diagnosis

The diagnosis of ALS is largely a clinical one relying on the presence of upper and lower motor neurone signs, progressive disease and the exclusion of other disease processes.

It can be challenging and given the prognosis cannot be made lightly, this often leads to a delay in diagnosis.

The revised El Escorial World Federation of Neurology criteria can be used to help diagnose ALS. As described in the paper by Brooks et al (2000), the diagnosis of ALS requires the presence of:

  • Evidence of LMN degeneration by clinical, electrophysiological or neuropathologic examination,
  • Evidence of UMN degeneration by clinical examination and
  • Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination

Together with the absence of:

  • Electrophysiological or pathological evidence of other disease processes that might explain the signs of LMN and/or UMN degeneration, and
  • Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiological signs.

The paper goes on to describe further categories based on a clinical diagnosis. These are beyond the scope of this note but can be read in the paper via link above.

It is acknowledged that due to the heterogeneity of presentation and lack entirely conclusive testing no diagnostic system is perfect. Other proposed diagnostic protocols include the Awaji criteria as well as a more recent proposal by Shefner et al (2020).

Management

Though ALS cannot be cured, appropriate management can improve both survival and quality of life.

Following the diagnosis patients (and their families) should be provided with appropriate information as well as emotional and psychological support.

Care should be provided with an appropriate MDT that includes a neurologist, specialist nurse, dietitian, physiotherapist, occupational therapist, respiratory physiologist, speech and language therapist and palliative care.

Medical therapy

Riluzole is the only drug treatment shown to improve survival in patients with ALS. Another therapy Edaravone has been shown to slow patients functional decline.

Symptomatic management may be offered to patients affected by muscle cramps. Quinine or baclofen are amongst the options available. Breathlessness may be treated with opioid therapy.

Physiotherapy and nutrition

An exercise plan should be developed, tailored to the individual patient, and updated as the disease progresses.

Monitoring of nutritional status and weight is key. Dieticians can help to maintain per-oral nutrition for as long as is possible before a gastrostomy can be considered. Early gastrostomy can reduce the risk of complications.

Ventilation

Non-invasive should be discussed when appropriate, for example bilateral positive airway pressure (BIPAP) and can offer a significant survival benefit.

Invasive mechanical ventilation with a tracheostomy may be discussed but the use varies significantly between countries.

End-of-life planning

The opportunity to discuss end of life care should be offered at the time of diagnosis and as the disease progresses. Decisions regarding nutrition, invasive ventilation and resuscitation status can be had.

This can be formalised into an advanced care directive. The patient may also want to appoint a lasting power of attorney for both health and finances.

Prognosis

Death most commonly results from respiratory failure, with a median survival of 3-5 years after symptom onset.

The speed of disease progression varies between individuals. Male and younger patients tend to have a better prognosis, those with limb onset have longer survival than those with bulbar onset. Certain familial forms show more rapid progression.

Around 5-10% of patients live 10 years and rarely they may live 20 years or more following symptom onset.

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