Lou Gehrig was an American who played 17 seasons in major league baseball for the New York Yankees from 1923 to 1939. Gehrig was renowned for his prowess as a hitter and for his stamina – traits that earned him his nickname, “The Iron Horse”. He set several major league records during his career, including the most career grand slams (23) and most consecutive games played (2,130), a record that stood for 56 years and had been considered unbreakable.
When the Yankees began their 1939 training it was clear that Gehrig no longer possessed his once-formidable power. His running between bases was affected, and at one point he collapsed at the Yankees’ spring training park. By the end of spring training, he had not hit a home run. Throughout his career, Gehrig was considered an excellent baserunner, but as the 1939 season got underway, his co-ordination and speed had deteriorated significantly.
By the end of April, his statistics were the worst of his career. One journalist who often wrote about him said: “I think there is something wrong with him. Physically wrong, I mean. I don’t know what it is, but I am satisfied that it goes far beyond his ball-playing. I have seen ballplayers ‘go’ overnight, as Gehrig seems to have done. But they were simply washed up as ballplayers. It’s something deeper than that in this case, though. I have watched him very closely and this is what I have seen: I have seen him time a ball perfectly, swing on it as hard as he can, meet it squarely – and drive a soft, looping fly over the infield. In other words, for some reason that I do not know, his old power isn’t there… He is meeting the ball, time after time, and it isn’t going anywhere.”
In 1939 he was diagnosed with motor neurone disease (MND) – most commonly, amyotrophic lateral sclerosis (AML) – usually referred to as ‘Lou Gehrig’s disease’ in North America. This forced him to retire at age 36 and was the cause of his death two years later.
MND is a rare but devastating illness which leads to progressive paralysis and eventual death. Although rare, many patients are both aware and fearful of it, as there have been several high-profile media campaigns concerning it recently, and one Oscar-winning film.NICE released new guidelines for its recognition and management in February 2016 and a few of the new points relevant to primary care that have been included this year, are covered below.
MND is mostly a sporadic disease of middle and elderly life with patients usually presenting in their sixties and seventies. However, it can present in younger patients, usually in familial types. The classic form of the disease is ALS which tends to be focal in onset, with a particular group of muscles affected first. This occurs in three patterns; limb onset (most common), bulbar (20%) and respiratory onset.
Although the least common presentation, the wary clinician should be mindful that the effects of reduced respiratory function, such as excessive daytime sleepiness, fatigue, early morning headache or shortness of breath when lying down, may indicate the diagnosis. Another atypical presentation is altered cognitive functioning, including fronto-temporal dementia. If you suspect MND, you are recommended to refer immediately and specify the possible diagnosis in the referral letter. Contact the consultant neurologist directly if you think the person needs to be seen urgently.
The guidelines recommend you consider advance care planning and offer the person with MND the opportunity to discuss their preferences and concerns about end of life care at trigger points such as: at diagnosis, if there is a significant change in respiratory function, or if interventions such as gastrostomy or non‑invasive ventilation are needed. These are often very difficult conversations to have and you are reminded to be sensitive about the timing of discussions and take into account the person’s current communication ability, cognitive status and mental capacity. When planning care take into account the following prognostic factors, which are associated with shorter survival if they are present at diagnosis, such as speech and swallowing problems (bulbar presentation), weight loss, poor respiratory function, older age and shorter time from first developing symptoms to time of diagnosis.
For symptom control, discuss the available treatment options for muscle problems and take into account the person’s needs and preferences, and whether they have any difficulties taking medicine (for example, if they have problems swallowing). Specific medicines are recommended within the guidance but if these treatments are not effective, not tolerated or are contra-indicated, consider referral to a specialist service for the treatment of severe spasticity.
Synonyms: amyotrophic lateral sclerosis (ALS), Lou Gehrig’s disease (USA form – named for a famous baseball player who succumbed to the disease), Charcot’s disease, Charcot’s syndrome, Charcot’s sclerosis
Motor neurone disease (MND) is a rare but devastating illness which leads to progressive paralysis and eventual death. Although rare, many patients are both aware and fearful of it. It is therefore important in primary care to understand the presentation and to be able confidently to reassure worried patients who are unlikely to have a diagnosis of MND. A review of life-prolonging interventions, symptom-control and disease mechanisms is appropriate for non-specialists and outlined in this article.
Most cases of MND are due to ALS. However, other forms occasionally occur. These include:
- Progressive bulbar palsy – about 2 in 10 people with MND have this type. The muscles first affected are those used for talking, chewing and swallowing. See separate article Bulbar and Pseudobulbar Palsy for more details.
- Progressive muscular atrophy – this is an uncommon form of MND. The small muscles of the hands and feet are usually first affected, but muscle spasticity is absent.
- Primary lateral sclerosis – this is another rare type of MND. It mainly causes weakness in the leg muscles. Some patients with this type may also develop clumsiness in the hands or develop speech problems.
This is a degenerative condition that affects motor neurons, namely the anterior horn cells of the spinal cord and the motor cranial nuclei. It causes lower motor neurone (LMN) and upper motor neurone (UMN) dysfunction, leading to a mixed UMN/LMN picture of muscular paralysis, usually with LMN signs predominating. The cause of the disease is unknown, although 5% of those affected have a familial form of the disease due to a mutation in the superoxide dismutase-1 gene.
Current aetiological hypotheses focus on an abnormality of mitochondrial function causing oxidative stress in motor neurons. There may be several causes for such oxidative damage to motor neurons and the disease may just represent an end-stage phenotypic expression of these abnormalities.
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- MND is relatively uncommon with an annual incidence of about 2 cases per 100,000 population. Prevalence is about 5-7 per 100,000. General practitioners can expect to see one or two cases in their career.
- It can occur at any age but is more common in people aged over 50. The male to female ratio is 2:1.
- About 5-10% of cases are inherited.
- The mean age of onset is 43-52 years in familial and 58-63 years in sporadic cases of ALS.
- Male sex, increasing age and hereditary disposition are the main risk factors.
MND is mostly a sporadic disease of middle and elderly life presenting in the sixth and seventh decades. However, it can present in younger patients, usually with familial MND.
- The classic form of the disease is also called amyotrophic lateral sclerosis (ALS). It tends to be focal in onset, with a particular group of muscles affected first. This presents In three recognised patterns:
- Limb onset – by far the most common.
- Bulbar onset – 20% of cases.
- Respiratory onset – the least common.
- Presents with symptoms and signs of degeneration of the upper and lower motor neurons, leading to progressive weakness of the bulbar, limb, thoracic and abdominal muscles.
- Other brain functions, including oculomotor and sphincter function, are relatively spared, but may be involved in some patients.
- Cognitive dysfunction may occur and 5-15% of patients develop dementia, usually of frontotemporal type.
- The rarer variants of the disease can present in two ways:
- With pure UMN features (primary lateral sclerosis).
- With pure LMN features (progressive muscular atrophy).
Patients or their families often notice problems occurring in one or more of the patterns below:
- LMD dysfunction in the limbs manifests as weakness, atrophy, fasciculations and hyporeflexia. The thighs are often a site of marked fasciculation. Fasciculation can be difficult to distinguish from arterial pulsation, so consider if there is an underlying arterial course before defining twitching movements as fasciculation.
- UMN dysfunction manifests as weakness predominating in the arm extensors and leg flexors with evidence of hypertonia, hyper-reflexia and upgoing plantar responses; the bulbar muscles may also show spasticity with an exaggerated jaw jerk.
- Ocular, sensory or autonomic dysregulation signs are usually late features of the disease.
Diagnostic pointers in limb-onset MND
- Asymmetrical distal weakness frequently occurs.
- Brisk reflexes will occur in a wasted limb.
- There is an absence of major sensory symptoms and pain.
- There is a relentless progression of symptoms and signs.
This is of course a diagnosis which needs a great deal of careful consideration given the poor prognosis. Nevertheless, it is equally important to ensure that the diagnosis is not unduly delayed. One study found that the average time from suspected diagnosis to confirmation was one year. The authors called for greater educational input in primary and secondary care and a fast-track referral service.
Diagnosis should be made after consideration of the clinical signs and symptoms together with investigations to exclude other causes. Important diagnoses which may cause confusion are listed in the box under ‘Differential diagnosis’, below.
Because of the very variable clinical presentation, the diagnostic criteria below have been devised, taking into account investigations to confirm the diagnosis and refute other possible causes (revised El Escorial Criteria):
- Presence of:
- Evidence of LMN degeneration by clinical, electrophysiological or neuropathological examination.
- Evidence of UMN degeneration by clinical examination.
- 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 and pathological evidence of other disease processes that might explain the signs of LMN and/or UMN degeneration.
- Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiological signs.
The World Federation of Neurology (WFN) has proposed further revision in the light of advances in neurophysiological techniques which can accurately detect degenerative neurological changes. They recommend upgrading the neurophysiological findings and making them as significant as the clinical findings in the diagnosis of ALS.
The differential diagnosis is vast, dependent on the mode of presentation, clinical findings and comorbidities. Diagnoses of particular importance have been singled out in the box below with features which distinguish them from MND.
Important diseases that can mimic MND
- Benign cramp fasciculation syndrome:
- Fasciculation or cramps usually affecting large muscles (for example, calves).
- The fasciculation is more common after exercise or with lack of sleep.
- There is no wasting or weakness on examination.
- There is no progression over time.
- Cervical radiculomyelopathy (multilevel degenerative disease of the cervical spine):
- This can present with a mixture of LMN wasting and weakness and UMN brisk reflexes and spasticity signs.
- There is pain (localised to the neck or radicular) and sensory disturbance.
- There are no bulbar symptoms and signs.
- The absence of UMN signs above the LMN signs increases the possibility of this diagnosis.
- MRI scan of the cervical spine can confirm the diagnosis.
- Dual pathologies:
- A cervical myelopathy and a co-existent peripheral neuropathy can present as a mixed upper-lower motor neurone picture.
- Sensory signs and symptoms and absence of bulbar symptoms help to diagnose this.
- Neurophysiological assessment and imaging will confirm the diagnosis.
- Multifocal motor neuropathy with conduction block:
- Often presents in young or middle-aged men as unilateral distal upper limb weakness with little evidence of wasting initially.
- This is an important rare diagnosis to consider in differential diagnosis of MND.
- In the correct clinical context, it can be diagnosed or excluded only by careful neurophysiological evaluation looking for conduction block.
- It is treatable and has a markedly different prognosis than that for MND.
- Inclusion body myositis:
- An inflammatory myopathy which presents with distal weakness without sensory symptoms.
- Clinically long finger flexors are affected preferentially (unusual in MND).
- Electromyography (EMG) and occasionally muscle biopsy are needed to confirm the diagnosis.
- Inclusion body myositis has a more benign prognosis than MND.
The list below shows further conditions that may have similar clinical features:
There are no specific investigations that will confirm a diagnosis of MND. A range of investigations is carried out to confirm consistent features and exclude other possible pathologies, usually under the direction of a neurologist. It may take several months to decide that the clinical presentation, progression and investigation findings are consistent with the diagnosis. This cautious approach is understandable, given the prognosis of the illness and the devastation that being given the diagnosis may cause to a person’s life. The investigations below may be conducted during the course of making the diagnosis:
- Electrophysiological studies such as EMG and nerve-conduction studies (NCS) will show a characteristic pattern but require careful interpretation, along with a consideration of the clinical features. In MND, EMG shows fibrillation and fasciculations. The motor units are polyphasic and have high amplitude and long duration. NCS should show normal motor and sensory conduction in MND. More sophisticated techniques have prompted recommendations (Awaji-shima consensus recommendations for the application of electrophysiological tests, as applied to the revised El Escorial Criteria) that the electrophysiological findings should be given equal weight to the clinical findings in the diagnosis of the condition.
- CT and/or MRI scanning of the brain and spinal cord are useful in excluding other pathologies with similar presentations. Neuro-imaging is not yet considered to be sufficiently sensitive to assess responses to treatment but the European Federation of Neurological Societies recommends that it should be incorporated into the evaluation of research trials.
- Blood tests to exclude other conditions, such as vitamin B12 and folate levels, HIV serology, Lyme disease serology, creatine kinase assay, serum protein electrophoresis, anti-GM1 antibodies (multifocal motor neuropathy with conduction block), urinary hexosaminidase-A assay (Tay-Sachs) and a host of other more specialised tests for rare conditions.
- Muscle biopsy may be considered to exclude or to diagnose myopathic conditions.
Giving the diagnosis
Part of the management of MND is giving the diagnosis and explaining the condition in an appropriately sensitive and informative way. The following points have been made:
- This is a difficult task and time; experience and expertise are needed.
- Follow the well-established good practice principles of breaking bad news.
- Impart information honestly but without destroying hope.
- Maintain a positive emphasis on what can be done to help.
Although specialists lead the diagnostic and monitoring process, GPs have a large part to play in the day-to-day management of the symptoms arising from the condition and the side-effects of medication.
MND is an incurable condition that usually, although not always, leads to death within a few years, with a period of distressing disability preceding it. Thus, the mainstay of management is in supporting the patient, their family and carers through this process and in delivering palliative care at the appropriate juncture. The following measures are helpful in prolonging the survival of those with MND and in helping them to maintain a sense of health, well-being and control over their lives:
- A multidisciplinary approach involving GPs, primary care nurses, occupational therapists, physiotherapists, speech therapists, dieticians, respite care providers, home care workers, hospital physicians and neurologists, along with many others, is likely to best serve the patient, and effective communication between all the interested parties is essential.
- GPs are particularly well placed in ensuring that patients and their carers know where to get information about any social or financial support that may be required.
- Regular physical, occupational and speech therapy to maintain strength and utility of the affected motor functions and allow use of aids designed to overcome specific disability problems.
- Dietetic support to allow adequate hydration and nutrition whilst the patient is able to feed independently, or with the aid of carers.
- Insertion of a gastrostomy tube should be considered when the patient is no longer able to feed by mouth. Current practice is to offer the option of enteral feeding to patients, either through percutaneous endoscopic gastrostomy (PEG), percutaneous radiological insertion of gastrostomy, or nasogastric tube (with 10% weight lost or a body mass index below 18.5).
- Communication can be greatly enhanced by the use of picture-boards or more advanced IT-based solutions tailored to the individual patient’s needs and disabilities.
- When respiratory function is impaired, physiotherapy helps to clear pulmonary secretions and maintain respiratory health.
- Positive pressure ventilation may be used in patients who are no longer able to maintain adequate ventilation. This has been shown to improve quality of life and survival greatly. The machines are small and portable and various face masks are available . Patients quickly get used to wearing the masks overnight. In later stages some patients may use non-invasive ventilation (NIV) during the day, using a small nasal mask.
The greatest advance in treating MND has been the discovery of the beneficial effects of NIV, in which the patient uses a mask ventilator system (usually bilateral positive airway pressure) overnight during sleep.
National Institute for Health and Care Excellence (NICE) guidelines recommend:
- Discussion about NIV at the time of diagnosis and at appropriate opportunities thereafter.
- The patient should be assessed for the symptoms and signs of respiratory impairment at three-monthly intervals.
- Patients who meet the NICE criteria for treatment of their respiratory impairment should be offered NIV. However, if the patient suffers from severe bulbar impairment or severe cognitive problems related to their respiratory impairment, NIV should only be offered if the patient has sleep-related symptoms or hypoventilation.
- If commenced, acclimatisation should occur during the day.
- Regular treatment should be given at night, before and during sleep.
- Hours of use should be built up as necessary.
- In patients with cognitive impairment, issues of capacity and consent may need to be considered.
- Riluzole (a neuroprotective glutamate-release inhibitor) is the only drug of proven disease-modifying efficacy.
- Its effects are modest, probably only prolonging lifespan by between two and four months.
- It may have a more significant effect on prolonging tracheostomy-free survival.
- It appears to be well tolerated and of greater benefit the earlier it is started in the course of the disease.
- It has been shown to act by blocking muscle acetylcholine receptors.
- It was hoped that antioxidants might prove beneficial. However, a recent Cochrane review concluded that the use of antioxidants was not supported by currently available clinical trial data.
- Other medications may be used to treat symptoms of the disease; for example:
- Drooling may be reduced by the use of anticholinergics such as hyoscine.
- Muscle cramps and spasticity can be treated with agents such as diazepam, baclofen, tizanidine, phenytoin and quinine.
- Respiratory distress and the sensation of choking may respond to opioid medications but this must be balanced against their tendency to cause respiratory suppression; they are very useful to treat this symptom in the palliative phase.
- Depression associated with MND may respond to the use of antidepressant medications.
- Pain often goes under-recognised and undertreated. It is thought to be due to spasticity but other mechanisms may be operant. The antispasmodic agents listed above are usually helpful but non-steroidal anti-inflammatory drugs and opioids, such as oral morphine, subcutaneous diamorphine and fentanyl patches, are also utilised, particularly in the palliative phase.
End of life care
Inevitably, the disease will progress and both patients and carers may wish to discuss the terminal phase of the illness. Careful discussion about this at a pace determined by the patient, family and carers helps to shape what form care will take. Issues which frequently come up include:
- Hospice care – this may be useful in the later stages of the disease for respite.
- Advance directives – information on these can be given and this can help implementation of patients’ wishes.
- Management of symptoms – for example:
- Respiratory distress – this can be treated with opiates.
- Choking – lorazepam sublingually can quickly relieve choking episodes.
- Dyspnoea – if severe and prolonged, is an indication for subcutaneous morphine.
- Respiratory failure and death.
- Pneumonia due to infection or aspiration.
- Urinary tract infections.
- Spasticity and cramping of muscles.
- Loss of speech as a means of communication.
- Immobility and attendant disability.
- Complications of immobility such as skin infections/bedsores and ulcers.
- Cognitive deterioration is rare but is seen occasionally.
- MND is usually a rapidly progressive and fatal disease but the rate of progression is variable.
- Median survival is two to four years.
- End of life care with all that this implies needs a co-ordinated sensitive approach. More than 90% of patients die in their sleep, as a result of increasing hypercapnia (respiratory failure with or without pneumonia) and choking to death is not seen in clinical practice.
- There appears to be a small subgroup of patients (5-10%) surviving for a decade or more.