Clinical Spectrum of Motor Neuron Disorders.8
Clinical Spectrum of Motor Neuron Disorders.8
Clinical Spectrum of Motor Neuron Disorders.8
OF MOTOR NEURON
DISORDERS
KEY POINTS
Richard J. Barohn
ABSTRACT
The differential diagnosis of amyotrophic lateral sclerosis (ALS) includes a number of
acquired or inherited disorders causing degeneration of lower and/or upper motor
neurons. It is important to consider these diagnoses in the appropriate clinical
context because the prognosis is often better, and, in certain situations, specific
treatments may be available. Many of the inherited motor neuron syndromes have
characteristic clinical presentations that facilitate their recognition. Alternatively,
features of the clinical presentation may be atypical for ALS, which should lead to
investigation of alternative diagnoses. This chapter will review the clinical features of
motor neuron syndromes that comprise the differential diagnosis of ALS and will
provide guidelines for their diagnostic investigation.
Continuum Lifelong Learning Neurol 2009;15(1):111131.
Less common motor neuron syndromes that may present clinically with
progressive dysfunction of motor neurons are included in the differential
diagnosis of sporadic amyotrophic
lateral sclerosis (ALS). In many cases,
diagnostic confirmation of these disorders requires specific electrophysiologic,
serologic, or genetic tests that are not
necessarily routine, so the possibility of
the disorder must be suspected by the
clinician, primarily based on the clinical
presentation. The recognition of a somewhat atypical presentation for ALS, or,
in some cases, characteristic clinical
features of a distinct motor neuron syndrome will guide the astute clinician in
pursuing an alternative diagnosis to ALS
in the appropriate clinical setting.
DEFINITION/TERMINOLOGY OF
MOTOR NEURON DISORDERS
The terms amyotrophic lateral sclerosis (ALS) and motor neuron disease
Motor neuron
disease is
characterized
by degeneration
of upper
motor neurons
(UMNs)
(corticospinal
tract), lower
motor neurons
(LMNs) (anterior
horn cells and
cranial nerve
motor nuclei), or
both. ALS, in
which patients
have both
anterior horn cell
and corticospinal
tract dysfunction,
is the most
common form
of motor neuron
disease.
Progressive
muscular atrophy,
primary lateral
sclerosis (PLS), and
progressive bulbar
palsy are motor
neuron disorders
in which the
degeneration is
limited to the
LMNs, UMNs,
and bulbar
musculature,
respectively.
The differential
diagnosis, clinical
course, and
prognosis are
distinct for these
motor neuron
disease syndromes
compared with
ALS, making
their recognition
clinically important.
111
KEY POINTS
The El Escorial
criteria classify
ALS into definite,
probable, clinically
possible, and
clinically probable
categories based
on the number of
body regions with
clinical findings of
UMN and LMN
dysfunction.
In patients with
suspected ALS
who have
multisegmental
UMN and LMN
findings and
a progressive
course, without
significant
sensory or
sphincter
abnormalities,
further
laboratory
studies are
unlikely to yield
an alternative
diagnosis.
112
FIGURE 5-1
TABLE 5-1
"
"
Hyperparathyroidism
Vitamin E deficiency
Copper deficiencya
Copper deficiencya
"
Structural Lesions
Brain stem tumor/massa
Polyradiculopathy/plexopathya
Plexopathya
Cervical spondylotic
myelopathya
Polyradiculopathy/plexopathya
Syringomyelia
"
Arnold-Chiari malformation
Syringomyeliaa
Leukodystrophies
(adrenoleukodystrophy,
adrenomyeloneuropathy,
metachromatic leukodystrophy)a
Leukodystrophies
(adrenoleukodystrophy,
adrenomyeloneuropathy,
metachromatic leukodystrophy)a
Kennedy bulbospinal
muscular atrophy
Hereditary ALS
Hereditary ALS
Spinocerebellar ataxias
Diffuse Lewy body disease
"
Hereditary ALS
Infection
HIV myelopathya
HIV myelopathya
Lyme diseasea
113
TABLE 5-1
Continued
"
Multiple sclerosis
Mononeuropathy multiplex
Dysimmune Diseases
Hexosaminidase A deficiency
Chronic inflammatory
demyelinating polyneuropathya
"
Vascular
Multiple cerebral infarcts
"
Malignant/Paraneoplastic
Lymphoma
"
Lymphoma
Other
Postradiation plexopathy
or motor neuron disease
"
Postradiation plexopathy
or motor neuron disease
Lambert-Eaton syndrome
Polymyositis
Myasthenia gravis
Lambert-Eaton syndrome
b
Polymyositis
Inclusion body myositis
Limb-girdle dystrophyb
Limb-girdle dystrophy
Distal myopathyb
Distal myopathy
114
KEY POINTS
In patients
with suspected
ALS and a typical
clinical
presentation,
laboratory
studies to
exclude other
diagnostic
possibilities may
be very limited.
More extensive
laboratory
testing should
be reserved for
more atypical
presentations
pure UMN
or LMN
syndromes,
disease of early
onset or
prolonged
duration,
evidence of
a coexistent
systemic illness,
or the presence
of sensory
or urinary
symptoms.
In typical ALS
presentations,
the yield of a
lumbar puncture
for CSF
examination
is low. CSF
evaluation
is reserved
for patients
in whom
meningeal
inflammatory
or infiltrative
disease is
suspected
clinically.
115
KEY POINT
116
Case 5-1
A 54-year-old woman presented with a 2-year history of progressive gait
dysfunction and lower limb weakness and stiffness. She initially noted
bilateral foot numbness and gait unsteadiness. Whereas the numbness
persisted for several months and then resolved, her gait unsteadiness
worsened and she noted stiffness in her legs. During the ensuing months,
she developed leg weakness and muscle thinning, developing a right
footdrop 10 months from onset of symptoms followed by a left
footdrop 12 months later. She required the use of a walker. She had noted
left-hand weakness for the past 3 months. She had no bowel or bladder
difficulties and had only intermittent sensory complaints (transient
paresthesias in the hands and feet).
Examination showed prominent atrophy of the anterior and posterior
leg compartments bilaterally. The patient had a completely flail right foot
and severe weakness of dorsiflexion and plantar flexion of the left foot
(2/5). Proximal muscle strength was normal, but muscle tone was increased.
There was moderate atrophy of the intrinsic muscles of the left hand,
with grade 4- strength. The right hand was normal. Muscle stretch reflexes
were very brisk with spread but absent at the ankles bilaterally. She
had bilateral Babinski signs. Sensory examination showed impaired light
touch, pain, and vibration in a stocking-glove distribution (to midcalf
and wrists).
Electrodiagnostic testing revealed unobtainable motor responses in the
peroneal and tibial nerves and normal motor responses in the upper
extremity. Sensory responses were normal in the upper limb, but the sural
sensory nerve action potential was low amplitude. EMG showed acute and
chronic neurogenic changes in a multisegmental distribution in the upper
and lower limbs.
MRI studies of the cervical, thoracic, and lumbosacral spine were normal.
CSF evaluation was normal. Extensive laboratory evaluation showed a
normal vitamin B12 level and moderate anemia (hemoglobin 9.2). The
patient had an undetectable serum copper level (less than 0.10 mg/mL),
low serum ceruloplasmin (7.8 mg/dL), and elevated serum zinc level
(2.5 mg/mL). She was placed on oral copper gluconate (3 mg/d). Six
months later, her neurologic symptoms had stabilized with some mild
improvement in left-hand function.
Comment. Most reports of the neurologic manifestations of copper
deficiency describe a myeloneuropathy with prominent sensory symptoms,
sensory ataxia, and varying degrees of spastic paraparesis. This patient had
clear evidence of LMN dysfunction both clinically and on electrodiagnostic
studies. Although her sensory symptoms were never persistent, they were
associated with some degree of sensory dysfunction on examination and
mildly abnormal sensory nerve action potentials on electrodiagnostic
testing. This was correctly judged to be atypical for sporadic ALS, and a
more extensive laboratory workup revealed the correct diagnosis.
KEY POINTS
A clinical
diagnosis of
ALS is supported
by evidence
of denervation
(LMN
dysfunction) on
needle EMG
in at least two
of the following
regions:
brainstem
(bulbar/cranial
motor neurons),
cervical,
thoracic, or
lumbosacral
spinal cord.
MRI of the brain
and/or spinal
cord is done to
look for
evidence of a
tumor, syrinx,
herniated
cervical spinal
disk, or cervical
spondylosis with
spinal cord
compression.
Cervical MRI is
particularly
important in
patients with
limb disease and
no bulbar
findings to
exclude cervical
radiculomyelopathy.
Muscle biopsy is
rarely necessary
in most cases of
ALS but may
be considered
if there is a
suspicion of
myopathy
based on
clinical or
EMG findings.
117
KEY POINT
118
The clinical
manifestations
of PLS include
adult onset,
progressive leg
weakness
and spasticity,
spastic bulbar
palsy, and
hyperreflexia
without sensory
signs. Spastic
weakness
may progress
asymmetrically.
esterase stains and chronic denervation with reinnervation, with fiber type
grouping and grouped atrophy, supports the diagnosis of LMN disease in a
region. This information, however, usually can be obtained through the EMG,
and muscle biopsy is not needed.
Rarely, inclusion body myositis
(IBM) can be misdiagnosed initially as
ALS because of the asymmetric onset.
The needle EMG can have both neurogenic and myopathic motor units in
IBM. Usually the pattern of weakness
in IBM is so typical, with wrist and
finger flexor and knee extensor involvement, that there should be no
confusion with ALS. However, occasionally it may be difficult at the
bedside and with the EMG to differentiate patients with IBM from patients
with ALS, particularly if the IBM patient
has another cause for UMN findings,
such as cervical spondylotic myelopathy. In this setting, a muscle biopsy is
useful. The biopsy in IBM should show
a chronic myopathy with endomysial
inflammation and rimmed vacuoles in
muscle fibers.
PRIMARY LATERAL SCLEROSIS
Jean-Martin Charcot first reported PLS
in 1874, calling it primary sclerosis of
the lateral columns (Rowland, 2001).
He noted the paucity of pathologic
evidence and the inability to know
conclusively that LMN signs would not
appear over time. These concerns,
which made it difficult to categorize
PLS as a distinct disease entity, still
apply in the modern era. As he stated
in a public lecture, pathological investigations have not yet furnished any
proof, and hence the solution to the
problem remains in suspense. Meanwhile, the clinical description deserves
to exist alone (Charcot, 1883).
The caution voiced by Charcot as to
whether PLS is a distinct entity was
reiterated by Kinnier Wilson (1940) in
his authoritative textbook of neurology:
to the increasing awareness noted earlier that MND may reflect one feature of a more general neurodegenerative process.
As illustrated by Case 5-2, PLS tends
to follow a very slowly progressive
course, a key distinctive clinical feature compared with ALS. Most recent
reports indicate that patients were still
alive, with average duration at the time
of follow-up of 8 years. Whereas the
average life expectancy for patients
with ALS is about 3 years, longevity
data for PLS are incomplete. Among
PLS patients with reported deaths,
survival reports range from 1 to 15
years after onset.
EMG Findings
Although in pure PLS needle EMG
should be normal, the recently reported series and criteria allow for
electrophysiologic evidence of mild
denervation manifested as occasional
fibrillation and increased insertional
activity in a few muscles, but not
enough or to the degree seen in ALS.
For this reason, the presence of active
denervation (increased insertional activity, grade 1+ fibrillations, or positive sharp waves) or fasciculations or
decreased recruitment of motor units
in a few muscles does not necessarily
rule out PLS. However, this is a controversial issue for which clear consensus is lacking.
There are reports of patients initially thought to have PLS but subsequently diagnosed with ALS after
7 to 27 years of UMN involvement.
Gordon and colleagues (2006) identified a group of 29 patients with isolated UMN signs and no evidence of
LMN involvement clinically or on EMG.
Of that group, 13 went on to develop
EMG evidence of denervation as well
as clinical signs of LMN dysfunction.
Patients with a diagnosis of PLS and
minimal EMG changes seem to have
KEY POINTS
Bulbar symptoms
in PLS usually
manifest first as
dysarthria,
followed by
dysphagia,
and may evolve
to emotional
lability and
inappropriate
laughing or
crying
(pseudobulbar
affect).
Dysarthria can
progress to
anarthria.
Other reported
clinical features
in patients with
PLS include eye
movement
abnormalities,
urinary
dysfunction,
and cognitive
impairment.
PLS tends
to follow
a very slowly
progressive
course, a key
distinguishing
it from ALS.
Whereas the
average life
expectancy for
patients with
ALS is about
3 years,
longevity data
for PLS are
incomplete.
Among PLS
patients with
reported
deaths, survival
reports range
from 1 to
15 years
after onset.
119
KEY POINT
Needle EMG
findings in
PLS should
show no
evidence
of LMN
dysfunction.
However,
recently
reported series
and criteria
allow for
electrophysiologic
evidence of
mild denervation
manifest as
occasional
fibrillations
and increased
insertional activity
in a few muscles.
Case 5-2
A 55-year-old woman initially developed lower extremity stiffness
beginning with the right leg 10 years ago, which gradually progressed
to the point that she became wheelchair bound 6 years later.
Approximately 3 years ago, she noted the onset of a speech problem,
which worsened to the point that, 18 months later, her speech was
practically incomprehensible. She had difficulty with swallowing for the
past 2 years and ate mainly soft, pureed food. She denied bladder
incontinence but had significant constipation for years. She had no
family history of neurologic disease.
On examination, the patient had a severe spastic dysarthria. Tongue
protrusion appeared normal in strength, but tongue movements were
markedly slowed. No tongue atrophy or fasciculations were present.
There was bilateral weakness of upper and lower facial muscles. Mild
symmetric weakness of the distal upper extremity muscles with associated
spasticity and a severe spastic paraparesis were present. She was thin,
but no clear muscle wasting or fasciculations were present. Muscle stretch
reflexes were diffusely brisk (3+), and she had prominent finger flexor,
pectoralis, and jaw jerk reflexes. Sensation was normal.
MRI of the brain showed only deep white matter signal changes.
MRI of the cervical and thoracic spine was normal. NCS and EMG done
on three occasions were normal. Spinal fluid analysis was normal.
Human T-lymphotropic virus antibodies were not present in the serum
or CSF. Hematology, serum chemistries, genetic hereditary spastic
paraparesis, B12, and serum immunofixation electrophoresis studies
were all normal.
Comment. This patient initially presented with lower limb spasticity
with a slowly progressive course and subsequently developed a progressive
spastic dysarthria. Clinically, she had predominant UMN dysfunction,
with three previous electrodiagnostic studies failing to reveal LMN
involvement. The absence of significant muscle atrophy also indicated
that this patient most likely had PLS. It has been suggested that patients
with MND presenting with spasticity who do not develop limb wasting
within 3 years do not have the classic profile of sporadic ALS and most
probably have PLS. These patients likely will progress more slowly and live
longer than those with typical ALS.
120
more disability compared with PLS patients without EMG changes. Singer
and colleagues (2005) reported a
significantly decreased ability to ambulate independently in their patients
with PLS with minimal EMG changes,
even after controlling for increased
duration of illness in that group.
Gordon and colleagues (2006) noted
significant differences in scores on the
ALS Functional Rating Scale between
their clinically pure PLS group and the
UMN-dominant ALS group, with a
trend toward lower forced vital capacity and reduced time to disability in
the UMN-dominant ALS group.
Differential Diagnosis
The differential diagnosis for progressive corticospinal spasticity, alone or
together with corticobulbar spasticity,
is broad (Table 5-1). Many disorders,
such as inherited illnesses or conditions with sensory symptoms or more
generalized neurologic impairment,
could be eliminated readily after a
KEY POINT
The hereditary
spastic
paraplegias
merit particular
consideration in
the differential
diagnosis
of patients
presenting with
progressive
spastic limb
weakness. The
absence of
family history,
typical onset
in middle age
or later life,
and bulbar
involvement
would make
this possibility
less likely.
121
KEY POINTS
122
For patients
with progressive
purely UMN
symptoms
acquired in
middle age or
later, the two
main diseases
to consider are
ALS and PLS.
ALS is more
common and
is usually
the ultimate
diagnosis.
The distinction
between
an immunemediated
neuropathy,
such as
multifocal motor
neuropathy,
and motor
neuron disease
can usually
be readily
made on the
basis of a
thorough history
and neurologic
examination and
supported by
electrophysiologic
studies.
Patients with
an idiopathic
purely LMN
disorder are
typically referred
to as having
progressive
muscular atrophy
(PMA). A
significant
proportion of
patients with
PMA actually
have ALS and
just lack clinical
evidence of UMN
involvement.
1992). Autosomal recessive juvenileonset forms of ALS have been identified, related to mutations in the ALS2
gene, a gene coding for the GTPase
alsin (Kress et al, 2005). Of considerable
interest, mutations in this same gene
have been associated with autosomal
recessive cases of infantile ascending
HSP and juvenile PLS (Eymard-Pierre
et al, 2006; McDermott et al, 2006). It
remains unclear how mutations in the
same gene can lead to three very
different phenotypes; the age of onset,
however, is usually in the first 2 years
of life, unlike typical PLS.
For patients with exclusive UMN
symptoms acquired in middle age or
later, the two main diseases to consider are ALS and PLS. ALS is more
common and is usually the ultimate
diagnosis. If there is no or very
limited evidence of LMN involvement,
a tentative diagnosis of a PLS-spectrum
disorder can be made. In this
setting, patients can be informed that
the prognosis is better compared
with ALS and that the progression
is slow. Such patients require close
follow-up to determine whether LMN
signs develop.
Diagnostic Criteria
Recently suggested diagnostic criteria
for PLS are given in Table 5-2 (Singer
et al, 2007).
PURE LOWER MOTOR
NEURON SYNDROMES
The LMN syndromes are heterogeneous and consist of idiopathic
conditions similar to ALS, inherited
disorders, andof most interest
immune-mediated disorders (Tables
5-1 and 5-3). The difference in prognosis leads many clinicians to explore
the possibility of an immune-mediated
disorder in many patients with suspected ALS. The truth is that, in most
cases, the distinction between an immune neuropathy and MND can be
made readily on the basis of a thorough history and neurologic examination. The main immune-mediated disorders that are in the differential
diagnosis for MND (Table 5-1) are
chronic immune demyelinating polyneuropathy (CIDP), mononeuritis multiplex, and multifocal motor neuropathy. In CIDP and mononeuritis
multiplex, patients almost invariably
have sensory signs and symptoms. In
CIDP, diffuse hyporeflexia is a characteristic feature, and profound muscle
weakness may be accompanied by
little or no muscle atrophy (in contradistinction to MND). The latter also
may be the case for multifocal motor
neuropathy, particularly in the early
stages. Although patients with multifocal motor neuropathy may have
asymmetric weakness and fasciculations, careful examination will reveal
that the weakness is in the distribution of individual peripheral nerves,
rather than myotomal, as would be
expected for MND.
Patients with an idiopathic, purely
LMN disorder typically are referred to
as having PMA. It is clear that a significant proportion of patients with
PMA actually have ALS and just lack
clinical evidence of UMN involvement.
This is supported by autopsy series
showing UMN pathology in approximately 50% of patients with PMA
(Ince et al, 2003). Up to one-third of
patients with MND lack UMN signs
at presentation (Mortara et al, 1984).
A significant portion of patients
with PMA, if followed over time,
will develop UMN findings and then
can be diagnosed with ALS. In some
cases, UMN signs may have been
present before the patient is evaluated
but subsequently became undetectable because of progressive LMN loss.
During the lifetime of a patient with
PMA, evidence of UMN pathology
may be detected with MRI or transcranial magnetic stimulation (Sach et al,
TABLE 5-2
"
Clinical Features
Presence of:
Findings of UMN disorder on physical examination
Spasticity
Pathologic reflexes
Weakness, when present, in an UMN distribution
Regions of involvement
Limb (legs, arms, or both
Bulbar
Mixed limb and bulbar
Time course: 4 years or longer
Progressive
Age of onset: adult older than 20 years
Bladder symptoms due to UMN dysfunction may be present
Absence of:
LMN disorder on physical examination
Fasciculations
Atrophy
Sensory signs on physical examination
Family history of similar disorders
"
Laboratory Features
Supportive of:
Transcranial magnetic stimulation
Increased central motor conduction time
Decreased cortical excitability (eg, motor evoked potential cannot
be obtained)
Magnetic resonance spectroscopy findings in the motor cortex
Decreased NAA/creatinine ratio
Decreased NAA/choline ratio
Diffusion-tensor imaging findings in the posterior limb of the
internal capsule
Decreased fractional anisotropy
Increased apparent diffusion coefficient
123
TABLE 5-2
"
Continued
Laboratory Features
Exclusionary
Serologic evidence for etiology of myelopathy
Abnormal CSF
Evidence of structural abnormality or demyelinating disorder on
routine MRI of brain or spine
EMG
Abnormal motor or sensory nerve conduction studies
See classification section (below) for patients with EMG abnormalities
Any known HSP or alsin gene mutations
"
CSF = cerebrospinal fluid; EMG = electromyography; LMN = lower motor neuron; NAA =
N-acetylaspartate; PLS = primary lateral sclerosis; UMN = upper motor neuron.
Reprinted from Singer MA, Statland JM, Wolfe GI, Barohn RJ. Primary lateral sclerosis. Muscle Nerve
2007;35(3):291302. Copyright # 2007, with permission from John Wiley & Sons, Inc.
124
2004). Conventional MRI sequences
may indicate UMN involvement, but
more specialized modalities, such as
magnetic resonance spectroscopy, are
usually needed (Kalra and Arnold,
2003).
Opinions differ on how to refer to
patients with an acquired LMN syndrome. For patients presenting with
a clinical picture resembling ALS
asymmetric, progressive weakness
but lacking UMN findings, many clinicians will give a diagnosis of ALS. This
is based on the high incidence of UMN
TABLE 5-3
Brachial
Monomelic Amyotrophic
Amyotrophy Diplegia
3060
2050
3060
1535
3060
Duration
Months
to years
Years
Decades
Decades
Progression
over 2 to
3 years with
subsequent
stabilization
Years
Distribution
of Weakness
Asymmetric,
distal
Asymmetric,
distal
Symmetric, Symmetric,
proximal
proximal
Asymmetric,
restricted
to 1 to 2
extremities
Symmetric,
proximal upper
extremities
Absent
Absent
Absent
Absent
Absent
Present
Present
Present
Present
Present
AR (SMN
gene)
XR
(CAG
repeats)
Sporadic
Sporadic
ALS
Inheritance
Distinct
Features
Gynecomastia, Male
predominance
diabetes,
impotence,
infertility
Preservation
of respiratory
and bulbar
function
patients LMN syndrome. Although patients may have a genetic cause for
their weakness, if there is no family
history and no gene defect identified,
their diagnosis may be classified as PMA.
However, certain clinical features, such
as symmetric and proximal weakness
with legs weaker than arms, would favor
SMA over PMA.
Several different LMN syndromes
have been described. Although overlap occurs, there are distinguishing
aspects with regard to age of onset,
etiology, site of involvement (regional
predilections and restrictions), progression, and mortality (Table 5-3).
125
KEY POINTS
126
PMA comprises
approximately
10% of
patients with
motor neuron
disease, being
slightly more
common in
men, with
an earlier
mean age of
onset. Patients
receiving the
diagnosis of
PMA represent
a mixed group:
patients who
have ALS
but lack
clinical features
of UMN
involvement as
well as patients
with a purely
LMN disorder
(more favorable
prognosis).
In adult-onset
spinal muscular
atrophy,
patients
typically present
with symmetric
proximal or
generalized
weakness and
fasciculations,
with sparing
of the bulbar
and respiratory
muscles.
Inheritance
may be either
autosomal
dominant or
recessive.
KEY POINTS
Case 5-3
A 53-year-old man was referred for a second opinion regarding a diagnosis
of ALS. He reported progressive symmetric lower extremity weakness with
onset 5 years ago. He noted a prominent fatigable component to his
weakness, with worsening associated with prolonged use of the muscles.
More recently, he had noted shoulder weakness, difficulty swallowing, and
facial twitching. He reported significant recurrent muscle cramping since
his early 20s. He denied a family history of neurologic illness.
Examination showed bifacial weakness with nearly continuous facial
fasciculations, proximal greater than distal extremity weakness, areflexia,
and normal sensation. There was also weakness and atrophy of the
tongue, a mild nasal dysarthria, and significant axial weakness with
an exaggerated lumbar lordosis. A postural tremor was noted in the upper
extremities, and frequent fasciculations were observed in the arms and
legs. He had gynecomastia.
CBC and chemistries were normal. MRI of the brain and C-spine
were normal. Serum CK level was elevated at 2400 IU/L. EMG showed
widespread reinnervation changes and fasciculations in arms, legs, tongue,
and thoracic paraspinals, with minimal fibrillation potentials. Motor
NCS were normal, although somewhat borderline in amplitude, and
sensory responses were absent in the upper and lower limbs.
Genetic studies were positive for an expanded allele in the CAG repeat
region of the androgen receptor gene (44 CAG repeats; normal is fewer
than 30), confirming the diagnosis of Kennedy disease. The patient was
provided with genetic counseling because he had two adult daughters
who were potential carriers of the genetic mutation.
Comment. This patient presented with prominent weakness and
fasciculations of the lower facial and oromandibular muscles and
proximal limb weakness, with onset of symptoms in his late 40s.
The prominent fasciculations and the electrophysiologic findings of
multisegmental neurogenic disease led to the initial diagnosis of ALS.
However, the chronic course, symmetric weakness, sensory abnormalities
on electrophysiologic testing, and the excessively elevated serum CK
level were clearly atypical findings. Further investigation led to the
recognition of the prominent facial fasciculations, gynecomastia, and
upper extremity tremor as characteristic of X-linked bulbospinal
neuronopathy, or Kennedy disease, and appropriate genetic testing
was performed to confirm the diagnosis.
X-linked
bulbospinal
neuronopathy
(Kennedy
disease) presents
with a limb-girdle
distribution of
muscle weakness
and bulbar
symptoms with
onset typically
in the fourth
or fifth
decade of life.
Distinguishing
clinical features
include
facial/perioral
fasciculations,
gynecomastia,
hyporeflexia,
hand tremor,
and tongue
atrophy with a
characteristic
midline furrow.
Monomelic
amyotrophy
is a rare disorder
in which
motor neuron
degeneration is
limited to a
single or several
myotomes
(usually C5 to
T1) within a
single extremity.
Progression
usually occurs
for 1 to 3 years
followed by
disease stability.
The mean age of
onset is typically
20 to 35 years
with a male
predominance.
127
KEY POINTS
128
Flail arm
syndrome
is an MND
regional variant
consisting of
weakness
exclusively
confined to
the upper
extremities.
Average
survival is
approximately
5 years,
compared with
3 years for
patients with
ALS.
In the flail arm
syndrome
clinical
phenotype,
if weakness
remains
confined to
the arms
for at least
18 months,
usually no
clinically
significant
progression
outside of
the upper
extremities
occurs and
survival is quite
prolonged.
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