CME Neurology Clinical Medicine 2013, Vol 13, No 1: 97–100

Motor neurone Table 1. Investigation of suspected MND.

Essential: Additional in selected cases:
disease: diagnostic Full blood count, erythrocyte sedimentation Vitamin B12 and folate
rate (ESR) and C-reactive protein (CRP) Anti-acetylcholine receptor antibodies
pitfalls Full biochemical profile (including thyroid HIV and Lyme serology
function tests [TFTs] and Ca2⫹)
Lumbar puncture
Creatine kinase (typically normal or modestly
Muscle biopsy
elevated, ⬎1000 iu/l very unusual in MND)
Immunoglogulins and serum electrophoresis
Timothy L Williams, consultant neurologist
and honorary senior lecturer in clinical Electromyography and nerve conduction
studies
neurology
MRI of brain and spine as indicated by physical
Department of Neurology, Royal Victoria
signs
Infirmary, Newcastle upon Tyne

Motor neurone disease (MND) is an MND exist, but these are not useful in rou- disease of the cervical and/or lumbo-sacral
uncommon (incidence 2–4/100,000 per tine clinical practice. The significant varia- spine. Patients with degenerative disease
annum), rapidly progressive neurodegen- tion in site and speed of onset and progres- often have pain, which may be radicular.
erative disorder, with onset typically in the sion often leads to diagnostic delay.4 Although initial symptoms of spondylotic
sixth and seventh decades (range 20–90+, Furthermore, given the gravity of the diag- disease might be progressive, they may pla-
average age of onset 63 in the UK). It has an nosis, many physicians are hesitant to make teau, a feature not seen in MND.7 Imaging
invariably fatal outcome, usually from res- it fearing both a difficult consultation and will help to identify patients who have
piratory failure, with 50% of patients dying the possibility of missing an alternative and spondylotic disease, although as a further
within 30 months of symptom onset. The potentially treatable condition. With complication, many ALS patients will also
diagnosis of MND is clinical, although usu- increasing specialisation, it is now best have radiological evidence of degenerative
ally supported by investigations such as practice that the diagnosis of MND be spinal disease, which is likely to be clinically
electromyography and nerve conduction made by a neurologist with knowledge of irrelevant.
studies (EMG/NCS), imaging and blood and access to appropriate support services.
work (see Table 1).1–3
Lower motor neurone syndromes
Amyotrophic lateral sclerosis (ALS) is the
Classical ALS phenotype of MND affecting the limbs
most common form of MND, and is char-
acterised by the often synchronous degen- The key presenting feature of MND is Misdiagnosis is more common when the
eration of upper motor neurones (UMN) progressive, painless weakness, and thus symptoms affect only the LMN, with a
and lower motor neurones (LMN). Other the list of potential differential diagnoses is diagnostic error rate for MND approaching
clinical phenotypes exist, including a pure long (see Table 2). Despite this, and the 20%.8 Importantly, several MND mimics
UMN variant (primary lateral sclerosis, clinical variability discussed above, the are potentially amenable to treatment or
PLS), a pure LMN variant (progressive misdiagnosis rate for MND is relatively low have a significantly more benign prognosis
muscular atrophy, PMA) and an initially at 7–8%.5,6 (see Table 3). The prompt referral of such
isolated bulbar muscle variant (progressive The most common ALS mimic is degen- patients to specialist neurological services
bulbar palsy, PBP). Diagnostic criteria for erative spondylotic myeloradiculopathic for assessment is thus important. Even in

Table 2. Mimic syndromes considered in the differential diagnosis of MND.

Genetic disorders Spinal muscular atrophy, Kennedy’s disease, hexosaminidase deficiency, mitochondrial disease,
triple A (Allgrove) syndrome, polyglucosan body disease, hereditary spastic paraparesis and
adrenomyeloneuropathy
Toxicities or metabolic disorders Radiation myelopathy, thyrotoxicosis, hyperparathyroidism, lead poisoning, mercury poisoning and
copper deficiency
Infective disease Post-polio syndrome, Lyme disease and HIV disease
Immunological or inflammatory syndromes Paraproteinaemic neuropathy, conduction block neuropathy, Sjogren’s syndrome, inclusion body
myositis, gluten sensitivity, myasthenia gravis and polymyositis
Structural disease Spondylotic myelopathy, base of skull lesions, foramen magnum lesions, intrinsic or extrinsic cord
tumours, and lumbo-sacral radiculopathies
Miscellaneous disease Cramp-fasciculation syndromes, paraneoplastic disease, lymphoproliferative disease and
paraneoplastic neuromuscular syndromes

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Table 3. Generalised or focal single (monomelic) limb onset lower motor neurone syndromes mimicking MND.
Brachial neuritis Sudden onset typically idiopathic inflammatory condition affecting the brachial plexus, characterised by
severe pain followed by weakness and wasting. Usually monophasic and self-limiting with good (albeit
often incomplete) recovery. Can be painless, bilateral and selectively involve phrenic nerve(s). Also known
as Parsonage–Turner syndrome.
Hirayama’s disease Also known as benign juvenile onset monomelic amyotrophy of the upper limb or focal segmental spinal
muscular atrophy. Can progress for 1–3 years and then static without progression or recovery. Sub-clinical
involvement of other arm or (less often) lower limbs apparent on EMG/NCS. So-called ‘cold paresis’ and
obique amyotrophy of the forearm can be characteristic. MND is typically more rapidly progressive with
subsequent respiratory and bulbar involvement. Most commonly seen in Japan and the Indian
subcontinent.
Motor neuropathy with conduction Rare, with onset typically under the age of 60. Conduction block not always easily demonstrable on EMG/
block9 NCS. Often disproportionate weakness in non-wasted muscles (muscle not denervated). Can have positive
anti-ganglioside GM1 autoantibodies.
Chronic inflammatory demyelinating Rarely presents as a pure motor phenomenon that results in focal or generalised weakness, with LMN signs
polyneuropathy and a significant elevation of cerebrospinal fluid protein. EMG/NCS should satisfactorily distinguish this
condition from MND.
Cervical radiculopathy See main text and references.7 Can occur without pain.
Kennedy’s syndrome Slowly progressive LMN syndrome, typically with prominent bulbar involvement. Tongue wasting
disproportionate to dysarthria, and lower facial (mentalis) fasciculation characteristic. Sensory (as well as
motor) neuronopathy is common. Non-motor features include partial feminisation with gynaecomastia
and small testes. Associated with near-normal life expectancy.
Radiation radiculopathy Sometimes also myelopathy. Often males with testicular cancer or women with cervical cancer. Para-aortic
nodal irradiation includes the distal spinal cord and cauda equine in the treatment field. Predominantly
motor syndrome caused by radiation-induced endarteritis.
Distal myopathy or inclusion body Typically slowly evolving symmetrical weakness (MND demonstrates rapid evolution and asymmetry).
myopathy (IBM) Weakness distal or characteristic involvement of quads (with wasting) and long finger flexors in IBM.
Dysphagia also seen with IBM. Creatine kinase modestly elevated x2–10 of normal range. EMG of both
distal myopathy and IBM can have ‘neurogenic’ features. Mis-diagnosis of MND in up to 13% of case.20

expert hands, serial assessment is often can present as predominantly distal LMN therapy in pure LMN conditions.11 Distal
required to allow accurate diagnosis, and weakness in the limbs and should be consid- and inclusion body myopathies (IBM)
the importance of clinical follow up cannot ered in the differential, particularly as bulbar should also be considered (see below and
be overstated. dysfunction often follows limb involvement Table 3).12,13
by many years10 (Table 3). Pure motor
forms of chronic inflammatory demyeli-
Generalised weakness Focal onset limb (regional)
nating polyneuropathy (CIDP) occur and
syndromes
Kennedy’s syndrome9,10 (also known as are the reason why some specialists advocate
X-linked spinobulbar muscular atrophy) a trial of intravenous immunoglobulin The focal onset of weakness in a single limb
(monomelic disease, typically LMN in
character) is a common presentation of
Key points MND. In this setting, however, the differen-
tial diagnosis is broad and includes a
Weak and wasted muscles with retained reflexes is highly suggestive of MND until
proven otherwise. Consider the diagnosis when faced with progressive painless
number of potentially treatable or more
weakness in patients over the age of 50. benign conditions (such as multifocal motor
neuropathy with conduction block14) (Table
Consider degenerative spinal disease, especially if the signs (and symptoms) can be 3). The key to the correct diagnosis of MND
attributed to a focal lesion.
is the recognition of progressive weakness
Monomelic or bilateral limb onset MND is common, but other more benign and and the evolution of physical signs of mixed
potentially treatable conditions exist and should prompt further assessment. motor system degeneration (i.e. UMN and
LMN signs in one or more limb).
Beware the diagnosis of MND in patients in whom dysphagia outweighs dysarthria.

Fasciculation without progressive weakness, particularly if symptomatic, is a common Bilateral lower limb LMN paresis
and usually benign phenomenon.
Although an increasingly recognised and
KEY WORDS: MND, diagnosis, pitfall, mimic, misdiagnosis relatively benign MND phenotype

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Fig 1. Imaging of patients with dysphagia greater than dysarthria.

(a) Midline T2 weighted sagittal MR head. This patient presented with
12 months of increasing dysphagia without dysarthria. There were no
abnormalities on examination. Extensive assessment by
gastroenterology, ENT, upper gastro-intestinal surgery and
investigation (endoscopic examination, barium swallow and blood
work) had failed to yield a diagnosis. MR imaging was requested to
exclude a structural lesion as a cause for dysphagia. The imaging
demonstrated a large midline clival meningioma, which was
successfully removed by surgery. The patient has a residual left facial
palsy, but near normal swallow. (b) Representative non-enhanced
CT brain head from a patient who presented with the abrupt onset of
mild dysphasia and right-sided weakness, followed over the next
48 hours by complete aphagia. Although initial CT imaging
demonstrated infarction of the left operculum, repeat CT imaging
24 hours later (shown here) demonstrated bilateral infarcts
representing the opercular or Foix–Chavany–Marie-syndrome
(dysphagia, dysarthria, drooling and facial weakness, often with limb
sparing), which is seen as a result of stroke, infection and occasional
neurodegenerative disease. Supportive treatment and temporary
naso-gastric tube feeding resulted in a good functional recovery.

(historically referred to as the polyneuritic bulbar onset MND patients will develop (but no dysarthria). The unusual history
variant of MND or ascending paralysis), symptoms and signs of limb involvement prompted a request for imaging.
such a presentation can lead to significant within 12 months of bulbar symptoms.1–3
diagnostic delay. Lumbo-sacral degenerative Almost without exception, the dysarthria Vascular disease
spondolytic disease, pure motor neuropathy/ associated with MND precedes and out-
neuronopathy11 and radiation (myelo) radic- weighs any dysphagia. Diffuse vascular disease is often consid-
ulopathies15 are included in the list of differ- ered in the differential diagnosis of MND,
ential diagnoses, as are distal myopathies and although such patients will typically have
Structural disease symptoms and signs beyond that of a pure
IBM. Detailed investigation and follow up,
with serial EMG/NCS examinations and Where dysphagia exceeds dysarthria, clini- motor system disorder. MND can be ini-
sometimes muscle biopsy should ultimately cians should be prompted into a careful tially misdiagnosed as a stroke, but the
lead to accurate diagnosis. search for an alternative diagnosis. In my progression of symptoms should prompt
experience (of more than 800 incident cases reconsideration, and emphasises the
of MND), such a presentation (dysphagia importance of follow up. Focal vascular
Bulbar and corticobulbar disease in the brainstem is very unlikely to
greater than dysarthria) of MND has
syndromes result in isolated dysarthria and dys-
occurred only twice. The patient repre-
Of patients with MND, 20–25% will present sented in Fig 1a was referred by gastroenter- phagia, and will usually be associated with
with bulbar dysfunction. Typically, such ology with dysphagia of unknown cause long tract (sensory and/or motor) signs.

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 CME Neurology

Occasional rare vascular syndromes can and unlikely to represent disease. 7 Chiles BW 3rd, Leonard MA, Choudhri HF,
cause diagnostic difficulty. Fig 1b illus- When fasciculation is persistent, it can Cooper PR. Cervical spondylotic myelop-
athy: patterns of neurological deficit and
trates a patient who presented with sub- represent benign muscle cramp or fascic-
recovery after anterior cervical decompres-
acute (over two days) dysphagia and dys- ulation syndrome. Patients can be reas- sion. Neurosurgery 1999;44:762–9.
phasia. The diagnosis, confirmed on sured, although EMG/NCS might be 8 Visser J, van den Berg-Vos RM, Franssen H
imaging, was of the opercular or Foix– required.18,19 Certainly muscle fascicula- et al. Mimic syndromes in sporadic cases of
Chavany–Marie syndrome. tion without weakness should be consid- progressive spinal muscular atrophy.
Neurology 2002;58:1593–6.
Other neurodegenerative conditions can ered a benign phenomenon, although
9 Finsterer J. Bulbar and spinal muscular
cause dysphagia and, although rare, can observation over time (sometimes atrophy (Kennedy’s disease): a review. Eur J
lead to misdiagnosis (e.g. progressive supra- 6 months or more), might be required to Neurol 2009;16:556–61.
nuclear palsy and Lewy body disease16). confirm that conclusion. 10 Atsuta N, Watanabe H, Ito M et al. Natural
history of spinal and bulbar muscular
atrophy (SBMA): a study of 223 Japanese
Neuromuscular transmission (NMT) patients. Brain 2006;129:1446–55.
Summary 11 Kimura A, Sakurai T, Koumura A et al.
disorders
The misdiagnosis of MND (particularly of Motor-dominant chronic inflammatory
The most common NMT disorder in the demyelinating polyneuropathy. J Neurol
the ALS phenotype), is uncommon. 2010;257:621–9.
context of isolated or near isolated bulbar
Atypical presentations, particularly of focal 12 Greenberg SA. Inclusion body myositis.
dysfunction (there can be mild limb girdle
onset and with pure LMN or UMN signs, Curr Opin Rheumatol 2011;23:574–8.
weakness in NMT disease and MND) is 13 Mastaglia FL, Lamont PJ, Laing NG. Distal
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myasthenia gravis (MG). Characterised by myopathies. Curr Opin Neurol
lenge, although perhaps reassuringly, treat-
fatigable weakness of ocular, oculo-bulbar 2005;18:504–10.
able mimics are rare. A working knowledge 14 Vlam L, van der Pol WL, Cats EA et al.
and/or limb girdle muscles, MG is occa-
of potential alternative conditions and Multifocal motor neuropathy: diagnosis,
sionally misdiagnosed as MND and vice
MND diagnostic pitfalls should help to pathogenesis and treatment strategies. Nat
versa. Muscle fatigue, although considered Rev Neurol 2011;8:48–58.
reduce the misdiagnosis rate, particularly if
a characteristic feature of MG, occurs in 15 Bowen J, Gregory R, Squier M, Donaghy
the key points are considered.
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ders including MND. Brain imaging, EMG/ neuron syndrome neuronopathy or radicu-
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2 McDermott CJ, Shaw PJ. Diagnosis and
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18 Mills KR. Characteristics of fasciculations
exclusion of other conditions affecting BMJ 2008;336:658–62.
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NMT, such as MG. Pyridostigmine, a 3 Talbot K. Motor neuron disease: the bare
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4 Logroscino G, Traynor BJ, Hardiman O
ment of MG, can provide transient 19 Jansen PH, Joosten EM, Van Dijck et al.
et al. Descriptive epidemiology of amyo-
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symptom relief in MND.3,17 trophic lateral sclerosis: new evidence and
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20 Dabby R, Lange DJ, Trojaborg W et al.
Psychiatry 2008;79:6–11.
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5 Davenport RJ, Swingler RJ, Chancellor AM,
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Warlow CP. Avoiding false positive diag-
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6 Traynor BJ, Codd MB, Corr B et al.
fasciculation, typically affecting just one Amyotrophic lateral sclerosis mimic syn- Royal Victoria Infirmary, Newcastle
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