Mimics and Chameleons in Motor Neurone Disease
The anxious medical student, qualified clinician or other individuals (typically under 40 years of age) presenting with fasciculations is a common clinical encounter. While 'muscle twitching' was the most sensitive symptom-based keyword for internet search engines to suggest MND as a diagnosis, it is part of normal physiology. Exercise, anxiety, caffeine and alcohol may all provoke fasciculations, and approximately 10% of thyrotoxic patients display them floridly. It is our experience that those with MND typically do not perceive their fasciculations until pointed out by the physician or a partner and so, in contrast to benign fasciculations, they are rarely the presenting complaint.
In the absence of weakness or abnormalities of thyroid function or electrolytes, individuals aged less than 40 years can be reassured without resorting to electromyography (EMG) to avoid the small but highly damaging possibility of false-positives. Equally, however, most subspecialists will recall a small number of cases, typically men in their 50s or 60s, in whom the latency from presentation with apparently benign fasciculations to weakness (and then clear MND) was several years. Our impression is that a clue may be that the fasciculations of MND are often abrupt and widespread at onset in an individual previously unaffected by fasciculations in youth. The site of the fasciculations, for example, those in the calves versus abdomen, has not been shown to be discriminatory for a benign disorder. There is conflicting evidence as to whether the character of fasciculations differs neurophysiologically in MND. EMG is only 60% sensitive for MND, however, and should not be treated as a diagnostic test, but carefully weighed up in the context of the clinical features.
Cramps and stiffness are a frequent co-occurrence with otherwise benign fasciculations; in the absence of weakness, these may be labelled as cramp-fasciculation syndrome, which improves with carbamazepine. True neuromyotonia (Isaacs' syndrome) is an extremely rare cause of fasciculations, and serum antivoltage gated potassium channels are only 50% sensitive. The absence of weakness in both cases is the most useful reassuring feature.
Multifocal motor neuropathy with conduction block has a prevalence of only 0.6/100 000, which is 10 times rarer than MND. It is a pure motor neuropathy characterised by slowly progressive, asymmetrical and distal weakness. There is a male predominance (3:1 compared with 3:2 in MND), and a younger age at symptom onset (mean 40 years compared with 65 in MND), with no cases reported aged over 70 years. Wrist or finger drop are common initial symptoms, but a third of cases present in the lower limb. Weakness with very little wasting is the general rule, certainly in early disease, and this should always prompt consideration of an alternative diagnosis to MND. Reflexes are usually lost but can be retained, and even brisk in up to 20% of cases. The absence of bulbar involvement is a notable feature. Respiratory involvement is exceptional and limited to rare case reports of phrenic nerve involvement. Vocal cord paralysis occasionally occurs (personal communication—Dr Chris Allen, followed by personal experience—MRT), but overall multifocal motor neuropathy with conduction block is very slowly progressive and associated with a normal life expectancy. Demonstration of conduction block by an experienced neurophysiologist is diagnostic but not always detectable. Positive anti-GM1 ganglioside antibodies (though only 50% sensitive) and T2-hyperintensity of the brachial plexus (also low sensitivity, figure 2) may be helpful adjunctive tests. Early intervention with intravenous immunoglobulin may limit axonal loss, and so rate of progression.
(Enlarge Image)
Figure 2.
Multifocal motor neuropathy with conduction block. Hyperintense swollen right-sided nerve roots on cervical spine coronal MRI (left panel, modified with permission from71). It typically causes asymmetrical distal weakness, often involving finger extensors initially, but can progress to wasting and fixed flexion deformity, as in this patient, several years after symptom onset (right panel; for other images see [72]).
The Parsonage–Turner syndrome (neuralgic amyotrophy or brachial neuritis) typically presents with a history of severe unilateral neck, shoulder or arm pain in the absence of trauma, followed over weeks by progressive upper limb weakness and muscle wasting, often involving multiple nerve root territories. Up to 5% of cases may be painless, however. Lower limb variants are much less common. There is often a history of preceding viral illness or vaccination. In 10% of cases of neuralgic amyotrophy there is a family history, with half of these linked to a point mutation or duplication in the SEPT9 gene. The key to excluding MND is that the process of weakness and wasting clearly arrests, with variable and slow recovery over months to years. In 10% of cases there is a bilateral pathology, and a particular catch is the involvement of the phrenic nerves, producing diaphragm paralysis with orthopnoea.
Spinobulbar muscular atrophy, or Kennedy's disease, is a rare X-linked disorder (manifest only in men) associated with a trinucleotide repeat in the first exon of the androgen receptor gene. Patients typically develop symptoms in the 4th or 5th decade or life, involving a very slowly progressive LMN syndrome, with muscle cramps and initially weakness and wasting in the legs or bulbar region (figure 3). Fasciculations are common and, when present over the chin, highly suggestive. Reflexes are absent or reduced. There may also be signs of androgen insensitivity with gynaecomastia and reduced fertility. Though Kennedy's disease can result in significant disability in later years, including respiratory involvement, lifespan is typically normal. The genetic test is diagnostic. There is no effective treatment at present. The slow symmetrical progression, and distinctive clinical features, should make the distinction from MND straightforward.
(Enlarge Image)
Figure 3.
Marked bilateral tongue and hand wasting in Kennedy's disease. The clue to this case not being motor neurone disease was the very slow progression, lack of upper motor neurone signs, gynaecomastia and chin fasciculations.
A motor-predominant variant may account for up to a third of all cases of chronic inflammatory demyelinating polyradiculoneuropathy, which has a similar incidence to MND. It is distinguished by a relapsing and remitting course, and is predominantly symmetrical with clear demyelination electrophysiologically. There is a notable lack of response to corticosteroids, which favours initial treatment with intravenous immunoglobulin (Box 1).
Inclusion body myositis is very much rarer than MND, and is a slowly progressive painless myopathy with a characteristic predilection for wasting of the medial forearm and quadriceps muscles (figure 4). Typically patients are aged over 50 years, with 3:1 male to female ratio and in the overwhelming majority of cases it is an apparently sporadic disorder. At first, there is usually asymmetrical proximal lower limb or distal upper limb weakness. Dysphagia occurs in a third of patients and rarely may be the initial symptom. A biochemical clue may be a raised serum creatine kinase beyond what is reasonable for denervation, for example, >1000 IU/l, though it can be normal. EMG is a classic pitfall for the unwary as it can appear neurogenic with fibrillation potentials. The muscle biopsy is diagnostic when it shows characteristic rimmed vacuoles, with inflammatory change (the latter only in sporadic cases). Immunological therapies have not been systematically assessed, and studies report only limited effects. The natural history is one of relentless progression over years, with significant disability and probably a reduction in life-expectancy as a result. Interestingly, there are rare hereditary forms of inclusion body myositis, including those associated with both MND and frontotemporal dementia, through mutations in the gene for valosin-containing protein (VCP), and muscle biopsies in inclusion body myositis stain for TDP-43, the characteristic protein aggregating in the nervous system in MND. Inclusion body myositis might therefore be best considered a degenerative disorder of muscle.
(Enlarge Image)
Figure 4.
Typical bilateral medial forearm and quadriceps (right leg only in this case) wasting of inclusion body myositis. There is a characteristic rimmed vacuole within a muscle fibre histopathologically (with acknowledgement to Dr Waney Squier).
Occasionally patients present with asymmetrical, slowly progressive segmental weakness and wasting of the upper limb. Although labelled as 'asymmetrical spinal muscular atrophy' this is a purely descriptive term rather than a diagnosis, and there are several underlying causes. Hirayama's disease is a characteristic form of upper limb wasting that is seen almost exclusively in young men (16–25 years) from Asia (Japan, the Indian subcontinent and China). One of the most consistent features is the striking unilaterality in most cases, though 20% of patients have evidence of more modest involvement of the contralateral arm. The wasting and weakness characteristically involve muscles innervated by the C7–T1 segments. Thus, the shoulder girdle is usually spared and there is often a striking sparing of brachioradialis (C5,6) in the forearm, giving rise to an appearance which Hirayama called 'oblique amyotrophy'. Fasciculations appear to be rare. It was shown that progression appears to arrest within a few years and patients followed up for more than 20 years never go on to develop progression to other areas of the motor system. In addition to weakness and wasting, patients may describe worsening of their symptoms in cold weather. There is a debate about whether this condition represents a focal form of primary LMN degeneration (ie, a focal form of spinal muscular atrophy) or a local consequence of chronic compression from a dural expansion in the cervical spine (figure 5).
(Enlarge Image)
Figure 5.
Flexion cervical spine MRI in Hirayama disease showing expansion of the dural venous plexus with presumed chronic ischaemic damage preferentially involving the anterior horn cells supplying the distal arm.
LMN-predominant upper limb presentations of MND frequently involve multiple myotomes, making cervical spine spondylotic polyradiculopathy an unlikely consideration. However, the characteristically slowly progressive, symmetrical LMN 'flail arm' variant of MND (also known as brachial diplegia or 'man-in-a-barrel' syndrome) is one subtype that can be mimicked by cervical spine pathology. Expansion of the dural space, presumed to occur after a previous traumatic cerebrospinal fluid (CSF) leak, results in cord compression and a slowly progressive, symmetrical upper limb proximal weakness with wasting, which may arrest spontaneously, though surgery has been undertaken in some patients (figure 6).
(Enlarge Image)
Figure 6.
This patient (shown from behind) presented with slowly progressive weakness and wasting of the shoulder girdles, neurophysiological evidence of denervation and slightly raised serum creatine kinase, all compatible with the 'flail arm' variant of motor neurone disease. MRI (inset) of the cervical spine showed expansion of the dural space posteriorly with forward compression of the spinal cord and presumed chronic damage to the anterior horns cells. His progression arrested spontaneously.
Radiotherapy to the pelvis and para-aortic lymph nodes for testicular and gynaecological tumours may lead to an LMN syndrome which often lacks sensory symptoms. The latency to developing symptoms may be decades (33 years in one case—MRT), and is thought to be mediated by a vasculopathy; thus, the history of exposure must be specifically sought (figure 7). The condition is usually very slowly progressive but may lead to significant disability and eventual sphincter involvement. The equivalent brachial plexus syndrome, typically following breast cancer, usually occurs with a more recent history of exposure and is more easily differentiated from MND by the presence of pain.
(Enlarge Image)
Figure 7.
Radiation-induced lumbar radiculopathy. This patient presented with a slowly progressive right leg weakness and wasting more than 30 years after radiotherapy to the right para-aortic nodes for testicular cancer (radiotherapy tattoos shown circled over abdomen).
With the hope of near global eradication of poliomyelitis, there are few infectious agents that target the LMN. Although poliomyelitis was once common, there is no evidence of anything more than a coincidental relationship when MND develops in someone previously affected by poliomyelitis. HIV has been linked to a very rare distal LMN syndrome, but prominent sensory features are typically a clue in HIV-related neuropathies.
Facial-onset sensory motor neuropathy is a very rare neurodegenerative disorder presenting in a slightly younger age group than MND, typically with trigeminal sensory loss, but also associated with wasting, weakness and fasciculation of the tongue and later respiratory muscle weakness. It is arguably more a mimic of syringobulbia. Progression is slow and immunomodulatory therapy has no effect.
LMN-only Signs
Benign Fasciculations
The anxious medical student, qualified clinician or other individuals (typically under 40 years of age) presenting with fasciculations is a common clinical encounter. While 'muscle twitching' was the most sensitive symptom-based keyword for internet search engines to suggest MND as a diagnosis, it is part of normal physiology. Exercise, anxiety, caffeine and alcohol may all provoke fasciculations, and approximately 10% of thyrotoxic patients display them floridly. It is our experience that those with MND typically do not perceive their fasciculations until pointed out by the physician or a partner and so, in contrast to benign fasciculations, they are rarely the presenting complaint.
In the absence of weakness or abnormalities of thyroid function or electrolytes, individuals aged less than 40 years can be reassured without resorting to electromyography (EMG) to avoid the small but highly damaging possibility of false-positives. Equally, however, most subspecialists will recall a small number of cases, typically men in their 50s or 60s, in whom the latency from presentation with apparently benign fasciculations to weakness (and then clear MND) was several years. Our impression is that a clue may be that the fasciculations of MND are often abrupt and widespread at onset in an individual previously unaffected by fasciculations in youth. The site of the fasciculations, for example, those in the calves versus abdomen, has not been shown to be discriminatory for a benign disorder. There is conflicting evidence as to whether the character of fasciculations differs neurophysiologically in MND. EMG is only 60% sensitive for MND, however, and should not be treated as a diagnostic test, but carefully weighed up in the context of the clinical features.
Cramps and stiffness are a frequent co-occurrence with otherwise benign fasciculations; in the absence of weakness, these may be labelled as cramp-fasciculation syndrome, which improves with carbamazepine. True neuromyotonia (Isaacs' syndrome) is an extremely rare cause of fasciculations, and serum antivoltage gated potassium channels are only 50% sensitive. The absence of weakness in both cases is the most useful reassuring feature.
Multifocal Motor Neuropathy With Conduction Block
Multifocal motor neuropathy with conduction block has a prevalence of only 0.6/100 000, which is 10 times rarer than MND. It is a pure motor neuropathy characterised by slowly progressive, asymmetrical and distal weakness. There is a male predominance (3:1 compared with 3:2 in MND), and a younger age at symptom onset (mean 40 years compared with 65 in MND), with no cases reported aged over 70 years. Wrist or finger drop are common initial symptoms, but a third of cases present in the lower limb. Weakness with very little wasting is the general rule, certainly in early disease, and this should always prompt consideration of an alternative diagnosis to MND. Reflexes are usually lost but can be retained, and even brisk in up to 20% of cases. The absence of bulbar involvement is a notable feature. Respiratory involvement is exceptional and limited to rare case reports of phrenic nerve involvement. Vocal cord paralysis occasionally occurs (personal communication—Dr Chris Allen, followed by personal experience—MRT), but overall multifocal motor neuropathy with conduction block is very slowly progressive and associated with a normal life expectancy. Demonstration of conduction block by an experienced neurophysiologist is diagnostic but not always detectable. Positive anti-GM1 ganglioside antibodies (though only 50% sensitive) and T2-hyperintensity of the brachial plexus (also low sensitivity, figure 2) may be helpful adjunctive tests. Early intervention with intravenous immunoglobulin may limit axonal loss, and so rate of progression.
(Enlarge Image)
Figure 2.
Multifocal motor neuropathy with conduction block. Hyperintense swollen right-sided nerve roots on cervical spine coronal MRI (left panel, modified with permission from71). It typically causes asymmetrical distal weakness, often involving finger extensors initially, but can progress to wasting and fixed flexion deformity, as in this patient, several years after symptom onset (right panel; for other images see [72]).
Neuralgic Amyotrophy
The Parsonage–Turner syndrome (neuralgic amyotrophy or brachial neuritis) typically presents with a history of severe unilateral neck, shoulder or arm pain in the absence of trauma, followed over weeks by progressive upper limb weakness and muscle wasting, often involving multiple nerve root territories. Up to 5% of cases may be painless, however. Lower limb variants are much less common. There is often a history of preceding viral illness or vaccination. In 10% of cases of neuralgic amyotrophy there is a family history, with half of these linked to a point mutation or duplication in the SEPT9 gene. The key to excluding MND is that the process of weakness and wasting clearly arrests, with variable and slow recovery over months to years. In 10% of cases there is a bilateral pathology, and a particular catch is the involvement of the phrenic nerves, producing diaphragm paralysis with orthopnoea.
Spinobulbar Muscular Atrophy
Spinobulbar muscular atrophy, or Kennedy's disease, is a rare X-linked disorder (manifest only in men) associated with a trinucleotide repeat in the first exon of the androgen receptor gene. Patients typically develop symptoms in the 4th or 5th decade or life, involving a very slowly progressive LMN syndrome, with muscle cramps and initially weakness and wasting in the legs or bulbar region (figure 3). Fasciculations are common and, when present over the chin, highly suggestive. Reflexes are absent or reduced. There may also be signs of androgen insensitivity with gynaecomastia and reduced fertility. Though Kennedy's disease can result in significant disability in later years, including respiratory involvement, lifespan is typically normal. The genetic test is diagnostic. There is no effective treatment at present. The slow symmetrical progression, and distinctive clinical features, should make the distinction from MND straightforward.
(Enlarge Image)
Figure 3.
Marked bilateral tongue and hand wasting in Kennedy's disease. The clue to this case not being motor neurone disease was the very slow progression, lack of upper motor neurone signs, gynaecomastia and chin fasciculations.
Motor-predominant Chronic Inflammatory Demyelinating Polyradiculoneuropathy
A motor-predominant variant may account for up to a third of all cases of chronic inflammatory demyelinating polyradiculoneuropathy, which has a similar incidence to MND. It is distinguished by a relapsing and remitting course, and is predominantly symmetrical with clear demyelination electrophysiologically. There is a notable lack of response to corticosteroids, which favours initial treatment with intravenous immunoglobulin (Box 1).
Inclusion Body Myositis
Inclusion body myositis is very much rarer than MND, and is a slowly progressive painless myopathy with a characteristic predilection for wasting of the medial forearm and quadriceps muscles (figure 4). Typically patients are aged over 50 years, with 3:1 male to female ratio and in the overwhelming majority of cases it is an apparently sporadic disorder. At first, there is usually asymmetrical proximal lower limb or distal upper limb weakness. Dysphagia occurs in a third of patients and rarely may be the initial symptom. A biochemical clue may be a raised serum creatine kinase beyond what is reasonable for denervation, for example, >1000 IU/l, though it can be normal. EMG is a classic pitfall for the unwary as it can appear neurogenic with fibrillation potentials. The muscle biopsy is diagnostic when it shows characteristic rimmed vacuoles, with inflammatory change (the latter only in sporadic cases). Immunological therapies have not been systematically assessed, and studies report only limited effects. The natural history is one of relentless progression over years, with significant disability and probably a reduction in life-expectancy as a result. Interestingly, there are rare hereditary forms of inclusion body myositis, including those associated with both MND and frontotemporal dementia, through mutations in the gene for valosin-containing protein (VCP), and muscle biopsies in inclusion body myositis stain for TDP-43, the characteristic protein aggregating in the nervous system in MND. Inclusion body myositis might therefore be best considered a degenerative disorder of muscle.
(Enlarge Image)
Figure 4.
Typical bilateral medial forearm and quadriceps (right leg only in this case) wasting of inclusion body myositis. There is a characteristic rimmed vacuole within a muscle fibre histopathologically (with acknowledgement to Dr Waney Squier).
Asymmetrical Spinal Muscular Atrophy
Occasionally patients present with asymmetrical, slowly progressive segmental weakness and wasting of the upper limb. Although labelled as 'asymmetrical spinal muscular atrophy' this is a purely descriptive term rather than a diagnosis, and there are several underlying causes. Hirayama's disease is a characteristic form of upper limb wasting that is seen almost exclusively in young men (16–25 years) from Asia (Japan, the Indian subcontinent and China). One of the most consistent features is the striking unilaterality in most cases, though 20% of patients have evidence of more modest involvement of the contralateral arm. The wasting and weakness characteristically involve muscles innervated by the C7–T1 segments. Thus, the shoulder girdle is usually spared and there is often a striking sparing of brachioradialis (C5,6) in the forearm, giving rise to an appearance which Hirayama called 'oblique amyotrophy'. Fasciculations appear to be rare. It was shown that progression appears to arrest within a few years and patients followed up for more than 20 years never go on to develop progression to other areas of the motor system. In addition to weakness and wasting, patients may describe worsening of their symptoms in cold weather. There is a debate about whether this condition represents a focal form of primary LMN degeneration (ie, a focal form of spinal muscular atrophy) or a local consequence of chronic compression from a dural expansion in the cervical spine (figure 5).
(Enlarge Image)
Figure 5.
Flexion cervical spine MRI in Hirayama disease showing expansion of the dural venous plexus with presumed chronic ischaemic damage preferentially involving the anterior horn cells supplying the distal arm.
Cervical Polyradiculopathy
LMN-predominant upper limb presentations of MND frequently involve multiple myotomes, making cervical spine spondylotic polyradiculopathy an unlikely consideration. However, the characteristically slowly progressive, symmetrical LMN 'flail arm' variant of MND (also known as brachial diplegia or 'man-in-a-barrel' syndrome) is one subtype that can be mimicked by cervical spine pathology. Expansion of the dural space, presumed to occur after a previous traumatic cerebrospinal fluid (CSF) leak, results in cord compression and a slowly progressive, symmetrical upper limb proximal weakness with wasting, which may arrest spontaneously, though surgery has been undertaken in some patients (figure 6).
(Enlarge Image)
Figure 6.
This patient (shown from behind) presented with slowly progressive weakness and wasting of the shoulder girdles, neurophysiological evidence of denervation and slightly raised serum creatine kinase, all compatible with the 'flail arm' variant of motor neurone disease. MRI (inset) of the cervical spine showed expansion of the dural space posteriorly with forward compression of the spinal cord and presumed chronic damage to the anterior horns cells. His progression arrested spontaneously.
Radiation-induced Radiculopathy
Radiotherapy to the pelvis and para-aortic lymph nodes for testicular and gynaecological tumours may lead to an LMN syndrome which often lacks sensory symptoms. The latency to developing symptoms may be decades (33 years in one case—MRT), and is thought to be mediated by a vasculopathy; thus, the history of exposure must be specifically sought (figure 7). The condition is usually very slowly progressive but may lead to significant disability and eventual sphincter involvement. The equivalent brachial plexus syndrome, typically following breast cancer, usually occurs with a more recent history of exposure and is more easily differentiated from MND by the presence of pain.
(Enlarge Image)
Figure 7.
Radiation-induced lumbar radiculopathy. This patient presented with a slowly progressive right leg weakness and wasting more than 30 years after radiotherapy to the right para-aortic nodes for testicular cancer (radiotherapy tattoos shown circled over abdomen).
Infections
With the hope of near global eradication of poliomyelitis, there are few infectious agents that target the LMN. Although poliomyelitis was once common, there is no evidence of anything more than a coincidental relationship when MND develops in someone previously affected by poliomyelitis. HIV has been linked to a very rare distal LMN syndrome, but prominent sensory features are typically a clue in HIV-related neuropathies.
Grand Round Rarities
Facial-onset sensory motor neuropathy is a very rare neurodegenerative disorder presenting in a slightly younger age group than MND, typically with trigeminal sensory loss, but also associated with wasting, weakness and fasciculation of the tongue and later respiratory muscle weakness. It is arguably more a mimic of syringobulbia. Progression is slow and immunomodulatory therapy has no effect.
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