MND and MMN Flashcards
Multifocal Motor Neuropathy (MMN)
Acquired autoimmune demyelinating motor neuropathy
Associated with motor conduction block
Slowly progressive, distal motor neuropathy which progresses over many years
Anti-GM1 antibodies frequently raised
The condition presents with asymmetric muscle weakness, which is slowly progressive, and without sensory signs. Differential weakness of finger extension is a typical presentation, and reflects a pathological process which selectively affects particular motor fibres within a peripheral nerve. Weakness without wasting is another typical feature. Nerve conduction studies show areas of conduction block outside usual areas for compression. Intravenous immunoglobulin can produce a rapid improvement in weakness.
Example Question
A 44 year-old man presents to the neurology clinic. He complains of weakness in the right hand, which causes difficulty with tasks such as writing and dressing, and has also noted ‘twitching’ in his right forearm and hand. He cannot recall exactly when the symptoms first began but feels that they have certainly been present for at least six months, and that they have got worse.
He is otherwise fit and well. His only past medical history is well-controlled asthma. There is no family history of neurological disease.
Cranial nerve examination is normal. On examination of the right hand, there is weakness of extension of the the middle and ring fingers (2/5 on the MRC scale), but no discernible muscle wasting. Fasciculations are visible in the dorsal aspect of the forearm. On examination of the left hand, there is also some subtle weakness of extension of the ring finger (4/5 on the MRC scale). There is no weakness of wrist extension on either side and power in all other muscle groups is normal. For both hands, all the fingers extend when the wrist is passively moved into palmar flexion. All reflexes are normal and there are no sensory signs.
What is the most likely diagnosis?
> Multifocal motor neuropathy Chronic inflammatory demyelinating polyneuropathy Motor neuron disease (amyotrophic lateral sclerosis) Inclusion body myositis Ruptured tendon of extensor digitorum
MMN may sometimes mimic motor neuron disease (MND). Both feature weakness, wasting, and fasciculation, with relatively preserved reflexes, and normal sensation. However, certain features suggest one diagnosis over the other. For example, bulbar weakness is common in MND but rare in MMN. Depending on the form of MND, variable upper motor neuron signs may occur, contrary to MMN which is a purely lower motor neuron condition occurring in a distribution correlating with named peripheral nerves. Finally, whereas MND is usually fatal within 5 years, MMN is slowly progressive over decades and does not typically cause respiratory failure.
Chronic inflammatory demyelinating polyneuropathy(CIDP) typically causes a progressive sensory and motor neuropathy with loss of reflexes. CSF protein is elevation and nerve conduction studies show evidence of demyelination.
Inclusion body myositis characteristically causes weakness of finger flexion, as well as knee extension and ankle dorsiflexion. Affected muscles are wasted, and fasciculations do not occur as there is no denervation.
Rupture of extensor tendons often occurs in rheumatoid arthritis. The affected finger cannot be actively extended, and does not passively extend when the wrist is passively moved into palmar flexion.
MMN vs MND
MMN may sometimes mimic motor neuron disease (MND). Both feature weakness, wasting, and fasciculation, with relatively preserved reflexes, and normal sensation. However, certain features suggest one diagnosis over the other. For example, bulbar weakness is common in MND but rare in MMN. Depending on the form of MND, variable upper motor neuron signs may occur, contrary to MMN which is a purely lower motor neuron condition occurring in a distribution correlating with named peripheral nerves. Finally, whereas MND is usually fatal within 5 years, MMN is slowly progressive over decades and does not typically cause respiratory failure.
Motor Neurone Disease
Motor neuron disease is a neurological condition of unknown cause which can present with both upper and lower motor neuron signs. It rarely presents before 40 years and various patterns of disease are recognised including amyotrophic lateral sclerosis, progressive muscular atrophy and bulbar palsy
MND - Mx
Riluzole
prevents stimulation of glutamate receptors
used mainly in amyotrophic lateral sclerosis
prolongs life by about 3 months
Respiratory care
non-invasive ventilation (usually BIPAP) is used at night
studies have shown a survival benefit of around 7 months
Prognosis
poor: 50% of patients die within 3 years
Management of ALS involves an multidisciplinary team (MDT) approach. Don’t forget to organised Speech and Language Team (SALT) assessment: poor swallow and aspiration pneumonia can kill. Additionally, NIV should be considered to treat respiratory insufficiency in ALS, both to lengthen survival and to slow the rate of Forced Vital Capacity (FVC) decline. It has been shown to increase survival by around 205 days. Riluzole has been shown to slow disease progression in patients with ALS by around 2-3 months.
Unfortunately, riluzole is the only drug that has been proven to demonstrate a disease modifying effect in motor neurone disease, increasing survival from diagnosis from 12 to 15 months1. Although genetic studies have implicated superoxide dismutase-1 (SOD1) as a pathogenic mechanism for MND, other therapies to reduce oxidative stress have so far been unsuccessful, such as addition of vitamin E and N-acetylcysteine (NAC). Non-invasive ventilation is the only other therapy that seems to prolong life expectancy but only if the patient can tolerate greater than 4 hours of NIV per day and without severe bulbar dysfunction2. As a result, NIV is recommended by NICE3 and the American Academy of Neurology2 when the patient has developed signs of respiratory distress, type 2 respiraotry failure, forced vital capacity has decreased below 50% or the patient has reported orthopnoea. However, patients with severe bulbar palsy or cognitive impairment are excluded.
MND - Diagnosis and Mx - Example Queston
A 58 year old man progressively develops hand clumsiness, gait difficulty and dysphagia over several months. His voice has also become high pitched and nasal. Sensory examination has remained normal throughout. Plantars are up-going, with absent ankle reflexes bilaterally and wasting of the distal leg musculature. Which treatment has been shown to lengthen survival for the underlying condition?
Intravenous immunoglobulin Donepezil Pyridostigmine > Non-invasive ventilation (NIV) Steroids
The answer here is motor neurone disease (specifically Amyotrophic Lateral Sclerosis (ALS) in this case). There is mixture of diffuse upper motor neurone features (the up-going planters and pseudo-bulbar ‘Donald duck’ speech) along with lower motor neurone features (wasting and areflexia) . The giveaway that it is not other causes of mixed upper and lower motor neurone features e.g. cervical spine pathology/syringomyelia/conus medullaris lesion is the bulbar involvement.
NB: Always look for the presence of tongue fasciculations if you pick up a mixed upper and lower motor neurone picture. If they are evident, think ALS rather than these other causes as they are too low down anatomically to involve the tongue (and bulbar muscles).
MND - Features
Motor neuron disease is a neurological condition of unknown cause which can present with both upper and lower motor neuron signs. It rarely presents before 40 years and various patterns of disease are recognised including amyotrophic lateral sclerosis, progressive muscular atrophy and bulbar palsy
There are a number of clues which point towards a diagnosis of motor neuron disease:
- fasciculation
- the absence of sensory signs/symptoms*
- the mixture of lower motor neurone and upper motor neurone signs
- wasting of the small hand muscles/tibialis anterior is common
*vague sensory symptoms may occur early in the disease (e.g. limb pain) but ‘never’ sensory signs
Other features
doesn’t affect external ocular muscles
no cerebellar signs
abdominal reflexes are usually preserved and sphincter dysfunction if present is a late feature
Motor neurone disease is also associated with fronto-temporal dementia.
MND Ix
The diagnosis of motor neuron disease is clinical, but nerve conduction studies will show normal motor conduction and can help exclude a neuropathy.
Electromyography shows a reduced number of action potentials with an increased amplitude.
MRI is usually performed to exclude the differential diagnosis of cervical cord compression and myelopathy
MND - Diagnosis: Example Question
A 62 year-old man with a history of osteoarthritis, type II diabetes and mild dementia is seen in neurology clinic. He has a 2 month history of weakness in his right arm. He has also noticed that his voice has become softer. He is finding it hard to use door handles and open jars. On two occasions his wife has noticed him stumbling whilst walking.
On examination he has fasciculations over his right deltoid muscle and wasting of the interossei muscles of the right hand. There is 4/5 strength in right shoulder abduction on the Medical Research Council (MRC) scale. Limb reflexes are absent in the right arm but detectable elsewhere. Coordination is normal. Sensation is normal and Romberg’s test is negative.
What is the most likely diagnosis?
Compressive Cervical myelopathy Diabetic peripheral neuropathy > Motor neurone disease Multiple sclerosis Thoracic outlet syndrome
Arm weakness can have many causes, but in this case the voice is also affected as are the lower limbs.
Fasciculations imply lower motor neurone involvement and would make a diagnosis of multiple sclerosis unlikely. Cervical myelopathy or diabetic neuropathy would not explain the voice change.
Thoracic outlet syndrome would not affect the patients legs so the most likely diagnosis in this case is motor neurone disease.
Motor neurone disease is associated with fronto-temporal dementia.
MMN vs MND - How to Differentiate
Multifocal motor neuropathy with conduction block (MMNCB) patients are usually younger to middle-aged men who develop focal arm weakness in the distribution of a named nerve. It usually happens quite suddenly (e.g. over a week) and they are often mistaken as a stroke at first presentation.
For exam purposes, the key difference between these two conditions is the nerve conduction studies.
MMNCB shows conduction block. MND does not.
MMNCB is a demyelinating condition, much in the same way Guillain Barré or chronic inflammatory demyelinating polyneuropathy (CIDP) are. However, in MMNCB this demyelination is in segments of a nerve rather than affecting the whole nerve. Therefore, the action potentials (as well as being slowed because of demyelination) actually don’t get past the areas of conduction block.
The importance of doing nerve conduction studies is to decide whether a motor neuropathy is axonal (i.e. the axon itself getting damaged) or demyelinating. The demyelinating ones tend to be more easily and similarly treatable.
MMNCB, Guillain Barré, and CIDP are all good examples of demyelinating neuropathies, all of which therefore respond to intravenous immunoglobulin (IVIG).
MMN vs MND: Example Question
A 45 year old man develops weakness of the extensors in the wrist and digits of his left upper limb over a week. Over the next 2 months he also notices weakness of the small muscles of hands on the right side, and that he is progressively unable to dorsiflex his right foot. On examination, he has wasting and 2/5 power in the left wrist and digit extensors. On the right he has clawing of the right ring and little fingers along with wasting of the small muscles of the hand on that side (except the thenar eminence and the first two lumbricals, which are spared). He has a right foot drop along with wasting of the anterior tibial and perineal muscles on that side. Fasciculations are seen in all of the areas of weakness. Sensory examination and reflexes are normal, along with no clonus. Plantars are down-going. The remainder of the examination are normal. Nerve conduction studies show conduction block. What is first-line maintenance treatment for this condition?
Riluzole > Intravenous immunoglobulin Pyridostigmine Steroids Beta-inteferon
The answer here is the condition called multifocal motor neuropathy with conduction block (MMNCB). These patients are usually younger to middle-aged men who develop focal arm weakness in the distribution of a named nerve. It usually happens quite suddenly (e.g. over a week) and they are often mistaken as a stroke at first presentation. However, over several months additional named motor nerves become involved asymmetrically such that MMNCB may eventually look like motor neurone disease (MND) - the principle differential here (specifically the lower motor neurone progressive muscular atrophy form rather than the mixed upper/lower motor neurone ALS form). For exam purposes, the key difference between these two conditions is the nerve conduction studies. MMNCB shows conduction block. MND does not. MMNCB is a demyelinating condition, much in the same way Guillain Barré or chronic inflammatory demyelinating polyneuropathy (CIDP) are. However, in MMNCB this demyelination is in segments of a nerve rather than affecting the whole nerve. Therefore, the action potentials (as well as being slowed because of demyelination) actually don’t get past the areas of conduction block. The importance of doing nerve conduction studies is to decide whether a motor neuropathy is axonal (i.e. the axon itself getting damaged) or demyelinating. The demyelinating ones tend to be more easily and similarly treatable. MMNCB, Guillain Barré, and CIDP are all good examples of demyelinating neuropathies, all of which therefore respond to intravenous immunoglobulin (IVIG).
Note that the nerves involved in this particular case are the left radial nerve, right ulnar nerve, and right common perineal nerve.
Bulbar Sx - Diagnosis: Example Question
A 57-year-old man presents with slurred speech. He was brought in by ambulance as his daughter was concerned when she came to visit and found his speech to be abnormal. On questioning, the patient has not noticed any changes; but the daughter has noticed that he has been drooling and been having difficulty eating for several months. She has not noticed a change in his memory or cognitive function but has been concerned that he has been laughing out of place in conversations. On examination, the patient has slight slurred speech, mild dysarthria and the tongue appears to move abnormally. His limbs are normal on examination, as is the remainder of his cranial nerve examination. What is the most likely diagnosis?
Myotonic dystrophy Stroke > Motor neuron disease Multiple sclerosis Syringobulbia
The correct answer is motor neuron disease. This a male patient in his 50s who has developed evidence of bulbar signs without any sensory or peripheral involvement. The chronic history makes a stroke less likely, whilst the progressive nature, his age and sex makes multiple sclerosis less likely. The absence of sensory loss or weakness of the arms makes syringobulbia less likely whilst myotonic dystrophy would have more peripheral signs. This is motor neuron disease presenting with bulbar features.
MND - Diagnosis: Example Question with Red Herring
A 69-year-old retired accountant was seen in the neurology clinic having been referred by his GP. He presented with a three-month history of malaise and weakness. The weakness initially affected his legs, and at times he felt that his legs would not support him standing up. Over the course of the last month, however, he also noticed weakness in his hands, especially his left hand. This was particularly noticeable when he rode his motorbike when he felt that his fingers were not strong enough to apply the brakes. In addition, his wife remarked that his speech had changed in tone though he did not have any difficulties with understanding or expressing speech. His past medical history comprised hypertension, hypercholesterolaemia, depression and hypothyroidism. His medication regimen included amlodipine 5mg OD, atorvastatin 20mg ON, citalopram 20mg OD and levothyroxine 125mcg OD. He also remarked that he had been referred by his GP to the fast track gastroscopy clinic and was pending an appointment for new onset difficulty in swallowing food over the last month. He did not smoke and did not consume alcohol. Upon a systems review, he denied the presence of other symptoms though he did admit to loosing 3kg of weight since the onset of his symptoms.
On examination, he appeared cachectic with obvious dysarthria. His blood pressure was 128/78 mmHg and his heart rate was 78bpm. Examination of his cranial nerves revealed the presence of tongue fasciculations with tremulous lips and an absent jaw jerk reflex but was otherwise unremarkable. Examination of his peripheral nervous system revealed small muscle intrinsic wasting of both hands, as well as wasting of his thigh muscles. The tone was reduced in his lower limbs but increased in his upper limbs. He had obvious weakness of all muscle groups, with a grade 4/5 weakness in his lower limbs and proximal upper limb and a grade 3/5 weakness in his distal upper limbs. Fasciculations were present in his thighs and forearms. Both upper and lower limb reflexes were brisk with downgoing plantars. Examination of sensation was normal. Examination of the cardiovascular, respiratory and gastrointestinal systems was unremarkable.
Investigations conducted by the GP prior to referral are as follows:
Hb 111 g/l Platelets 99 * 109/l WBC 12.2 * 109/l ESR 18 mm/hr CRP 6 mg/l ANA positive Rheumatoid factor negative
Which one of the following interventions is most likely to be of benefit?
Mitoxantrone > Riluzole Rivastigmine Methotrexate Azathioprine
This patient has motor neurone disease (MND), with clinical evidence of amyotrophic lateral sclerosis and bulbar palsy. Of the above options only riluzole, an anti-glutamate, has been shown to be of any benefit and is suitable for the amyotrophic lateral sclerosis variant of MND. The presence of ANA antibodies is a red herring; it is thought to be present in up to 15% of healthy individuals and is not associated with MND.
MMN-CB (Multifocal Motor Neuropathy with Conduction Block)
Multifocal motor neuropathy with conduction block
Multifocal motor neuropathy with conduction block (MMN-CB) is an acquired immune-mediated demyelinating neuropathy. Features of MMN-CB may resemble motor neuron disease but in contrast MMN-CB may respond well to intravenous immunoglobulin
MMN-CB: Example Question
A 78 year old male presents to you with progressive weakness in his arms. He first saw his GP about 4 months ago complaining of a weakness in his right wrist and was told he had carpal tunnel syndrome, for which he was placed on a waiting list to see the orthopaedic surgeons. Over the next 4 months, he noticed progressive weakness in his right wrist and in bending his right elbow. He noted his right hand was becoming increasingly wasted. Two months ago, he noted similar weakness in his left wrist. He reports no changes to sensation, normal speech and swallowing. On examination, cranial nerves were unremarkable.
Both hands were markedly wasted with significant loss of musculature and fasciculations bilaterally. Reflexes were muted in both upper limbs with negative Hoffman’s sign. Sensory examination in the upper limbs were unremarkable, he was unable to perform finger-nose examination. Examination of the lower limbs was also unremarkable but the patient felt a subjective weakness in both hip flexion. MRI imaging of the patients head and spine demonstrated no significant lesions. Nerve conduction studies demonstrated f waves and H reflexes, multiple focal areas of demyelination and motor neuropathic blocks.
What is the optimum management?
Intravenous cyclophosphamide > Intravenous immunoglobulin Intravenous methylprednisolone Plasma exchange Riluzole
The patient has presented with a pure motor peripheral neuropathy with mutilfocal areas of demyelination and motor block, with f waves and H reflexes suggestive of late motor responses to electrical stimuli, suggestive of multifocal motor neuropathy with conduction block (MMN-CB). MMN-CB is an immune-mediated disorder, commonly associated with anti-GM1 antibodies, typically presenting with asymmetric bi-brachial motor weakness without sensory or bulbar involvement, allowing the key distinction from motor neurone disease. MMN-CB is not responsive to steroids or plasma exchange, unlike chronic demyelinating polyneuropathy (CIDP), which typically involves sensory nerves too.
Cyclophosphamide may have some efficacy but is generally not used in MMN-CB due to its toxicity profile.
Riluzole is a drug for motor neurone disease.
MND and NIV - Example Question
A 64 year old gentleman presented to the neurology clinic for review. He had a history of motor neuron disease which had been progressing over the past five years. He had significant weakness in all of his limbs, and was dependent on a wheelchair. He took baclofen for relief of muscle spasms, and amitriptyline to reduce salivation, but was otherwise not on any medication. He mentions that in addition to his weakness continuing to progress he has been suffering from headaches in the morning. These were generalised and described as throbbing in nature. He also reported not feeling refreshed after sleep.
On examination there is generalised muscle wasting, with fasciculations in all limbs. Reflexes were absent, other than bilateral extensor plantar responses. Eye movements and fundoscopy are normal. Palatal movements were normal, and there was no significant dysphagia on swallow test.
Which intervention is most likely to confer the greatest survival benefit in this patient?
Riluzole Feeding via percutaneous endoscopic gastrostomy > Non-invasive ventilation Home oxygen therapy Prophylactic antibiotics
The morning headaches and lack of feeling refreshed after sleep are suggestive of carbon dioxide retention due to respiratory impairment in patients with motor neuron disease. Non-invasive ventilation improves quality of life and confers a survival benefit in patients with respiratory impairment in motor neuron disease.
Riluzole also offers a modest survival benefit in motor neuron disease (it is the only drug known to do so), prolonging life expectancy by on average two to four months. Given there is no evidence of dysphagia feeding via a percutaneous endoscopic gastrostomy is not indicated in this patient. Home oxygen therapy and prophylactic antibiotics are not routinely used in motor neuron disease.
