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Motor Neurone Disease

Overview

Motor neuron disease (MND) is a disorder that involves rapidly progressive degeneration of the upper and/or lower motor neurons (UMN, LMN). 

The most common form of MND is amyotrophic lateral sclerosis (ALS), which is 10% familial and 90% sporadic adult-onset.

The rarer subtypes of MND include progressive muscular atrophy (PMA) that affects LMNs and primary lateral sclerosis (PLA) that prinicipally destroys UMNs.

Irrespective of these distinctions, experts in the field have seemed to favor the suggestion that they will become ALS at some stage during the progression of disease.

The condition of MND is highly debilitating and it often carries a five-year mortality of 70% following the onset of symptoms.

Epidemiology

The worldwide prevalence of MND/ALS is frequently cited as 5-7 per 100,000 person-years. There are several epidemiological studies reported the presence of geographical variation, Caucasian and male predominance in the occurrence of disease.

However, these statistics may subject to change owing to the growing interest in research, the ageing population and the implementation of the Awaji-Shima recommendations as a replacement to the traditional Revised El Escorial criteria for diagnosing MND, which has been in use since 2006. 

How sensitive and specific are the two diagnostic tools?

The Awaji-Shima consensus recommendations are a set of combined clinical and neurophysiological tools that were shown to be 32.7% (60.7% versus 28%) more sensitive, but equally specific (95.9%), to the traditional Revised El Escorial criteria in a retrospective study by Douglas et al in 2010. A more recent systematic review and meta-analysis by Costa et al also echoed that the Awaji-shima are superior to the Revised El Escorial criteria and suggested that the use of the former may allow earlier diagnosis and patient entry into clinical trials in ALS.



Pathophysiology

Our current understanding of MND centres around the “excitatory hypothesis” of glutamate: a neurotransmitter which has the potential to cause flooding of calcium ions in the post-synaptic motor neurons; mitochondrial dysfunction and the formation of reactive oxygen species and proteases that are responsible for apoptosis of the motor fibres.

It was estimated that 15% of familial MND sufferers have chromosomal defects which produce functional superoxide dismutase (SOD), an antioxidant that counteracts neuronal destruction caused by free oxygen radicals.

The aetiology of sporadic MND is largely unknown. There is plentiful literature that suggests prolonged heavy cigarette smoking and exposure to organic solvents and heavy metals as modifiable risk factors for MND. However, further research is required in order to prove these hypotheses. 



Clinical features

Paralysis of the skeletal muscles is almost inevitable within five years of the diagnosis of MND/ALS. Disabling factors such as wrist drop, foot drop, cramps and spasticities in the upper and/or lower extremities cause major setback to patients' activities of daily living.

Bulbar symptoms, notably dysphagia, wasting of the tongue and reduced gag reflex are contributory to malnutrition, multiple choking episodes and aspiration pneumonia.

The fatigue of respiratory muscles is also well described as a risk factor for nocturnal hypercapnia and respiratory failure. The onset of acute ventilation insufficiency in patients inevitably requires consideration of NIV or ventilation. 

Differentiating UMN from LMN signs



MND does not affect motor neurons alone!

There is emerging evidence to suggest MND as a multi-system disorder that affects more than “just the motor components”. Several neuropsychological studies have estimated that almost half of all MND patients will demonstrate evidence of frontal lobe dysfunction as the disease progresses. Other than cognitive and behavioral impairments, case reports in MND have also reported elements of salivary dysfunction, and revealed evidence of reduced heart rate variation and denervation of the adrenergic cardiac fibres which are consistent with deregulation of the autonomic nervous system.

The denervation of Onuf’s nucleus (neurons located at the ventral horn of spinal cord at sacral region that are responsible for micturition and defaecation) that were evident on post-mortem studies would also suggest the likely involvements of bowel and bladder sphincters in MND.

The concurrent features of MND also include sensory disturbances, opthalmoplegia and parkinsonism. However, because of their relative rare presentation, it shall be of good medical practice to consider other aetiologies; and to perform the appropriate neuroimaging and electrophysiological studies before establishing the final diagnosis. 

Differential Diagnosis

The differential diagnosis for MND is huge. The conditions that are not to be missed:

  • Multi-focal motor neuropathy
  • Brainstem lesions from stroke or syrinx
  • Multi-level degenerative changes/ diseases of the cervical spine
  • Polymyositis, inclusion body myositis (IBM)
  • Benign fasciculation syndrome



Investigations

The diagnosis of MND is largely clinical. So far there is no single laboratory marker that can confirm MND. The use of electrophysiological studies (EMG/NCS) have been heavily weighed in the Awaji-shima consensus recommendations to increase the "true positives" for diagnosing ALS.

Lumbar punctures and neuroimaging techniques such as CT and MRI, are useful to exclude conditions that may micmic ALS but they are generally of limited value in the workup for MND.

The additional tests that may be required include:

  • FBC/ESR/U&E/Vitamin B12 & folate levels
  • TFT (?Thyrotoxicosis)
  • Anti-GM1 antibodies (?MMN)
  • CK +/- muscle biopsy (?Myositis)
  • Anti-acetylcholine receptor antibodies, anti-MUSK antibodies (?Myasthenia Gravis)
  • Androgen receptor gene mutation (?Kennedy's disease)
  • Anti-neuronal antibodies +/- CT chest/abdomen/pelvis (?Paraneoplastic)
  • Toxicology (?Heavy metal poisoning)
  • Syphillis serology (?Neurosyphillis)

Management

The care of MND patients should consist of experienced neurologists, general practitioners, specialist and community nurses and allied health care professionas such as physiotherapists and occupational therapists, speech and language therapists and dieticians. As patients are approaching their end-of-life, the options of palliative care should also be raised.

The following aims to review the three key aspects surrounding the care of patients with MND:

  • Symptomatic relief
  • Optimization of function 
  • Disease modifying therapy

Symptomatic relief

MUSCLE SPASTICITY AND CRAMP 

Spasticity is common in MND. The hyper-excited alpha motor neurons cause “tightness” and “stiffness” of the body extremities; and hence problems including joint contractures, poor coordination and difficulty in toileting. The fatigue or irritability of muscles may also cause cramps which can become very painful. 

Exercise such as stretching; strengthening and endurance may preserve soft tissue extensibility; improve myofibre remodeling, CNS adaptation and reduce inflammation of neurons in MND. With regard to therapeutics, the three most common skeletal muscle relaxants that we used in clinical practice are baclofen, tizanidine and benzodiazepine. Baclofen is a GABA agonist that is thought to improve muscle contraction, flexor spasms and disability. The agent can either be taken orally or be injected intrathecally for intractable case. Its oral preparation is commonly served as a comparator to benzodiazepine, which is also GABA agonistic; and tizanidine, a centrally-acting alpha 2 agonist in clinical trials. Clinically, they are all of similar efficacy but the side effects of drowsiness and worsening muscle weakeness are generally less frequent in patients with tizanidine.

Optimization of function

RESPIRATORY SUPPORT

Respiratory function is a strong indicator of function and survival. The diagnosis of MND should prompt early referral for assessment of patients’ peripheral oxygen saturation (SpO2), forced vital capacity (FVC), vital capacity (VC); and measurements of their sniff nasal inspiratory pressure (SNIP) or maximal inspiratory pressure (MIP) by the respiratory specialists. As according to NICE, patients should be enrolled into a 3 monthly review as surveilence for further deterioration.

 

Non-invasive ventilation (NIV)

Patients with irreversible deterioration of respiratory function, for instance, a drop in:

  1. FVC below 50% predicted or less than 80% with signs of respiratory compromise*; or
  2. SNIP/MIP of 40cmH2O or below 60 cmH2O with evidence of respiratory compromise*

should always warrant discussion about non-invasive ventilation (NIV) and other treatment options with patients and their careers. (* The signs of respiratory compromise include dyspnoea at rest, hypercapnia, nocturnal hypoventilation and orthopnea)

    The landmark randomized controlled trial (RCT) in NIV came from a single-centre in Newcastle, UK. In this study, 41 ALS patients with symptomatic hypercapnia or orthopnea with MIP below 80% predicted were randomized to receive either NIV (n = 22) with bi-level positive airway pressure (BIPAP; at mean inspiratory and expiratory pressures of 15cmH2O and 4cmH2O respectively) or standard care (n = 19). With clear study protocol and plans for follow-up, the study demonstrated significantly longer survival and more favorable QOL in patients who received NIV than those without by a median of 205 days (p = 0.0059). The lack of survival and functional benefits in patients who suffered poor bulbar function suggests that bulbar impairment is a poor prognostic indicator in MND.

    Additionally, NIV for at least four consecutive hours a day has been shown to delay the time for tracheostomy and mechanical ventilation (TV, MV). There has also been a suggestion that NIV could slow down the deterioration of FVC (3.5% and 8.3% reduction per month in NIV users and non-users respectively). However, as FVC is poorly related to other pulmonary function studies and symptoms of early respiratory deficiency, its correlation with the presumed benefits of NIV remains uncertain.

     

    Tracheostomy ventilation (TV)

    Tracheostomy generally serves two purposes in MND. It is either used to facilitate rehabilitation of patients who demonstrate slow weaning from invasive ventilation following critical illness or is done electively for those who progressively deteriorate or suffer bulbar and cognitive dysfunctions that impair their compliance on NIV. In comparison to NIV, TV is more complex, costly and involves a high level of support.

    The uptake of tracheostomy is hugely dependent on patient autonomy; healthcare funding and the geographical area that they reside. There are some low quality studies that suggest TV could extend life for longer than patients on NIV. Despite the higher survival rate, the loss of ability to communicate in patients that would inevitably occur around five year of the diagnosis; the risks of stoma infection, recurrent pneumonia and tracheo-oesophageal fistula have frequently sparked off debates on QOL and whether TV is worth initiating in the first place.

     

    Enteral nutrition (EN)

    Enteral feeding via a Percutaneous Endoscopic Gastrostomy (PEG) or Radiologically Inserted Gastrostomy (RIG) is often offered to patients with dysphagia.

    The uptake of EN is reported to be lowest in Italy (11-24%) and highest in Japan (21-60%). Although there is no consensus as to when enteral feeding should be initiated in MND; recurrent choking and gagging episodes, evidence of weight loss more than 10% of normal or evidence of clinical anorexia (BMI < 18kg/m^2) are generally triggers for EN.

    A FVC of 50% is often used as the reference value for safe gastrostomy. A FVC of more than 50% predicted is generally considered safe for the insertion of PEG. RIG requires less sedation and it is placed at FVC of 50% predicted or below. The lowest safety margin for RIG is yet determined by clinical trials.

    Despite extensive publications in the field, the benefits in survival and nutrition outcomes of patients with EN were only concluded as “tentatively favorable” by the most recent systematic review of 10 non-randomized trials in 2011. The study with the best methodological quality was a retrospective 26-centre study of 221 patients. Concerning survival statistics, the study demonstrated higher hazard ratios in those who received no PEG feeding; and with more rapid decline of their bulbar and respiratory function. The results of this study are also comparable with similar trials published in later years.

    DISEASE-MODIFYING THERAPY

    RILUZOLE

    Riluzole is the sole disease-modifying agent in MND. As a glutamate release antagonist, riluzole is proposed to reduce excitotoxicity through glutamatergic transmission in CNS. The most recent systematic review has shown that riluzole, if taken 100mg daily, prolong ssurvival for a median of two-to-three months but had negligible effect on muscle strength, bulbar and limb functions in patients who fall under the “definite” or “clinical probable” Revised El Escorial classification. 

    The pooled analysis of trials showed that Riluzole was generally tolerable in patients. Some rare side effects can occur, for example raised alanine transference (ALT) above five times of its upper limit in 4% of patients. The other rare abnormalities include anaemia, neutropenia, acute lung injury, hypersensitivity and pancreatitis.

    Summary

    MND is a rare but rapidly progressive degenerative disorder that has the potential to involve UMN, LMN and the rest of the nervous system. MND has no cure and no effective life-prolonging treatment. The mainstay of management should therefore focus on symptomatic relief, optimization of function and the preservation of patients' QOL.

    References and Suggested reading

    Sathasivam S. Motor neurone disease: clinical features, diagnosis, diagnostic pitfalls and prognostic markers. Singapore Med J. 2010 May;51(5):367-72 (http://smj.sma.org.sg/5105/5105ra1.pdf)

    Simmons Z. Management strategies for patients with amyotrophic lateral sclerosis from diagnosis through death (http://neurologiauruguay.org/home/images/manejoesclerosislateral.pdf)

    Rafiq MK, Proctor AR, McDermott CJ, Shaw PJ. Respiratory management of motor neurone disease: a review of current practice and new developments. Practical Neurology. 2012 June 1, 2012;12(3):166-76. (http://pn.bmj.com/content/12/3/166.abstract)

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