Você está na página 1de 21

CLINICAL SPECTRUM

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

(MND) often are used interchangeably,


but MND includes a spectrum of clinical
syndromes that result from degeneration of upper motor neurons (UMNs),
lower motor neurons (LMNs), or both
(Figure 5-1). ALS, in which patients
demonstrate evidence of both anterior
horn cell and corticospinal tract dysfunction, is the most common form
of MND.
Progressive muscular atrophy (PMA),
or Aran-Duchenne syndrome, is an example of an MND in which there is
exclusively LMN involvement. This disorder, which constitutes approximately
8% to 10% of patients with MND, is
slightly more common in men, with an
earlier mean age of onset than ALS.
Patients with PMA tend to have a much
better prognosis than patients with ALS,
and bulbar involvement is rare.
Primary lateral sclerosis (PLS), in
which only UMN degeneration occurs,
occupies the other extreme of the

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.

Relationship Disclosure: Dr Barohn has nothing to disclose.


Unlabeled Use of Products/Investigational Use Disclosure: Dr Barohn has nothing to disclose.

Copyright # 2009, American Academy of Neurology. All rights reserved.

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

111

" MOTOR NEURON DISORDERS

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

MND spectrum. PLS is a rare disorder


and, like PMA, is associated with a
prolonged course, with patients sometimes surviving for decades.
Progressive bulbar palsy (PBP) refers to a form of MND in which the
initial symptoms result exclusively from
bulbar dysfunction, which may be related
to either UMN or LMN degeneration or
both. Although the disease may remain
in this form for many years, it can progress rapidly to cause more generalized
signs and symptoms of ALS. For those
patients in whom the disease is confined
to the bulbar muscles for many years,
the term isolated bulbar ALS (IBALS)
(Dumitru et al, 2007) has been used.
The differential diagnosis, clinical
course, and prognosis are distinct for
PMA, PLS, and PBP compared with ALS,
making recognition of these clinical syndromes clinically important. The following sections will review the evaluation
and differential diagnosis for typical ALS,
PLS, and the pure LMN syndromes.
EVALUATION AND DIFFERENTIAL
DIAGNOSIS OF ALS
As discussed in the chapter Approach
to the Patient With Suspected Myasthenia Gravis or ALS: a Clinicians
Guide, the El Escorial criteria
(Brooks, 1994; Brooks et al, 2000)
classify ALS into definite, probable,
clinically possible, and clinically probable categories based on the number
of body regions with findings of UMN
and LMN dysfunction. Clinically defi-

Spectrum of motor neuron disorders.

nite ALS is defined on clinical evidence


alone and requires both UMN and
LMN findings in the bulbar region and
at least two spinal regions (cervical,
thoracic, lumbosacral) or UMN and
LMN signs in three spinal regions.
Clinically probable ALS is diagnosed
on clinical evidence and has UMN and
LMN signs in at least two regions, with
some UMN findings rostral to at least
one LMN finding. Clinically probable
laboratory-supported ALS is the presence of clinical signs of UMN and LMN
dysfunction in only one region, or
UMN signs alone in one region, and
LMN signs defined by EMG criteria
present in at least two regions, with
other causes excluded by neuroimaging and other laboratory tests. Clinically possible ALS consists of UMN and
LMN findings in one region or UMN
findings in two or more regions or LMN
signs rostral to UMN signs and insufficient electrodiagnostic, neuroimaging,
or clinical laboratory studies to support the diagnosis of clinically probable
laboratory-supported ALS. Other diagnoses must have been excluded to accept a diagnosis of clinically possible ALS.
In most patients, ALS does not
present as a diagnostic dilemma. In
patients with prominent UMN and
LMN findings and a progressive course
without significant sensory or sphincter
abnormalities, further laboratory studies
are unlikely to yield an alternative
diagnosis. Patients typically present with
bulbar or asymmetric limb weakness,
more prominent in distal than in proximal muscles. Atypical clinical features
should prompt the clinician to search
for alternative diagnoses (Table 5-1).
Laboratory Studies
For the patient with suspected ALS, a
clinical presentation consisting of both
UMN and LMN findings in a widespread distribution, no laboratory test
either proves or disproves the diagnosis. Experienced neurologists differ in

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TABLE 5-1

Differential Diagnosis for Motor Neuron Disorders

Combined Upper and Lower


Motor Neuron Disorder

"

Pure Upper Motor


Neuron Disorder

Pure Lower Motor


Neuron Disorder

Primary lateral sclerosis

Progressive muscular atrophy

Sporadic Motor Neuron Disease


Amyotrophic lateral sclerosis

Juvenile monomelic atrophy


Brachial amyotrophic diplegia
Leg amyotrophic diplegia

"

Metabolic, Nutritional, and Toxic Disorders


Hyperthyroidism

Cobalamin (B12) deficiencya

Heavy metal exposure

Hyperparathyroidism

Vitamin E deficiency

Cobalamin (B12) deficiencya

Copper deficiencya

Copper deficiencya

"

Structural Lesions
Brain stem tumor/massa

Cervical spondylotic myelopathya

Polyradiculopathy/plexopathya

Spinal cord tumor/mass/vascular


malformations, disc herniationa

Spinal cord tumor/mass/vascular


malformations, disc herniationa

Plexopathya

Cervical spondylotic
myelopathya

Foramen magnum tumor

Polyradiculopathy/plexopathya
Syringomyelia

"

Arnold-Chiari malformation
Syringomyeliaa

Degenerative and Hereditary Diseases


Polyglucosan body disease

Hereditary spastic paraparesis

Spinal muscular atrophy

Leukodystrophies
(adrenoleukodystrophy,
adrenomyeloneuropathy,
metachromatic leukodystrophy)a

Leukodystrophies
(adrenoleukodystrophy,
adrenomyeloneuropathy,
metachromatic leukodystrophy)a

Kennedy bulbospinal
muscular atrophy

Hereditary ALS

Hereditary ALS

Hereditary motor neuropathy


(distal spinal muscular atrophy)

Spinocerebellar ataxias
Diffuse Lewy body disease

"

Hereditary ALS

Infection
HIV myelopathya

HIV myelopathya

Lyme diseasea

Tropical spastic paraparesis


(human T-lymphotropic
virus type 1 infection)
Neurosyphilisa
Lyme disease

continued on next page

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

113

" MOTOR NEURON DISORDERS

TABLE 5-1

Continued

Combined Upper and Lower


Motor Neuron Disorder

"

Pure Upper Motor


Neuron Disorder

Pure Lower Motor


Neuron Disorder

Multiple sclerosis

Multifocal motor neuropathy

Stiff person syndrome

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

Myopathic and Neuromuscular Junction Disorders


Inclusion body myositisb
Myasthenia gravis

Lambert-Eaton syndrome
Polymyositis

Myasthenia gravis

Lambert-Eaton syndrome
b

Polymyositis
Inclusion body myositis

Limb-girdle dystrophyb

Limb-girdle dystrophy

Isolated neck or trunk


extensor myopathyb

Isolated neck or trunk


extensor myopathy

Distal myopathyb

Distal myopathy

Usually has sensory symptoms or signs.


With other causes for upper motor neuron signs, such as cervical spondylotic myelopathy or old stroke.

114

their choice of studies routinely ordered when the clinical diagnosis of


ALS is suggested. In general, very few
laboratory studies need to be done
before a diagnosis of ALS is rendered.
The purpose of laboratory studies is to
exclude other diagnostic possibilities,
and, in most cases, the testing required
is usually very limited. For patients
with a classic presentation as noted
above, routine chemistries, complete

blood count (CBC), serum creatine


kinase (CK), electrophysiologic testing,
and imaging studies of the spine/brain
commonly are performed. 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).

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

CBC and chemistry profiles generally


are performed as a screen for a systemic
illness but are rarely revealing in typical
ALS cases. Thyroid function tests often
are obtained to exclude hyperthyroidism because it can manifest rarely with
weakness, fasciculations, and hyperreflexia. Serum cobalamin (vitamin B12)
and copper levels are performed to
exclude combined systems degeneration, but these patients almost invariably have sensory symptoms and signs
(Case 5-1). If absolutely no sensory
symptoms or signs are present, it is
probably not necessary to obtain B12 or
copper serum levels. It may be helpful
to obtain a serum CK, which is usually
mildly increased in ALS but may be
normal. A CK level greater than 10 times
the upper limit of normal is suggestive
of a myopathy, such as polymyositis or
inclusion body myositis, rather than
ALS. Hypercalcemia, hypophosphatemia, and elevated parathyroid hormone
levels may suggest primary hyperparathyroidism. Rarely, patients with hyperparathyroidism can present with muscle
weakness. After removal of a parathyroid adenoma, some patients with
weakness have improved clinically but
other patients have had a progressively
fatal course, suggesting the coincidental occurrence of the two disorders
(Jackson et al, 1998). Based on this
experience, it is not necessary to obtain routine parathyroid hormone levels
in patients with suspected ALS unless
the serum calcium is elevated.
Laboratory studies also may include
serum protein electrophoresis with
immunofixation to screen for a monoclonal gammopathy because occasionally motor neuropathy occurs in patients
with lymphoma.
The presence of a monoclonal
gammopathy should prompt a hematology consultation for possible bone
marrow examination and consideration
of CSF examination for cytology. If
lymphoma presents with a motor neu-

ropathy presentation, however, an LMN


presentation usually predominates.
It is not recommended to perform a
lumbar puncture routinely for CSF
examination in typical ALS cases because the yield is low. For now, CSF
evaluation is reserved for patients in
whom meningeal inflammatory or infiltrative disease is suspected clinically.
In most cases, these patients will have
sensory symptoms, pain, and/or signs
of systemic illness. In the future, diagnostic CSF biomarkers may allow for
improved diagnosis of ALS, perhaps
leading to the ability to make a diagnosis definitively in early cases. Routine testing for heavy metals in the
serum or urine is not indicated unless
there is a high index of suspicion for
exposure.
In young-onset patients, particularly those under 40 years of age,
testing for a familial ALS syndrome
should be considered, even in the
absence of a family history (see the
chapter ALS Update: Signs of Progress, Reasons for Hope). In younger
patients with symmetric (proximal
greater than distal) weakness and no
UMN findings, serum hexosaminidase
A levels often are obtained to look
for late-onset GM2 gangliosidosis. In
patients with distal amyotrophy and
associated ataxia or dystonia, adultonset spinocerebellar ataxia should
be considered.
All patients with MND should undergo EMG and nerve conduction
studies (NCS). The purpose of electrophysiologic testing is to confirm the
presence of a multisegmental motor
axonopathy consistent with the clinical impression of ALS and to search for
evidence of an alternative diagnosis.
To support the diagnosis of ALS,
results of the NCS should be normal
or suggest degeneration of motor
axons without sensory involvement.
The EMG can be used to document
LMN involvement in a particular body

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.

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

115

" MOTOR NEURON DISORDERS

KEY POINT

116

All patients with


MND should
undergo EMG
and nerve
conduction
studies. The
purpose of
electrophysiologic
testing is to
confirm the
presence of a
multisegmental
motor
axonopathy and
to search for
evidence of an
alternative
diagnosis.

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.

region. The electrophysiologic findings


of motor conduction block or other
demyelinating features suggest the presence of a demyelinating neuropathy.
Accordingly, the NCS should evaluate

proximal segments of the nerve for


motor conduction block, which would
be suggestive of a demyelinating disorder such as multifocal motor neuropathy. Multifocal motor neuropathy is

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

characterized by slowly progressive asymmetric weakness, conduction block in


motor NCS, and occasionally elevated
GM1 ganglioside titers. This demyelinating neuropathy can superficially resemble ALS but has no UMN signs. Because
multifocal motor neuropathy patients
respond to IV immunoglobulin as therapy, appropriate diagnosis is critical.
Abnormal sensory NCS would suggest
an alternative diagnosis of a polyneuropathy, mononeuritis multiplex, or, rarely,
X-linked bulbospinal neuronopathy (see
discussion later in this chapter).
The needle examination is essential
to confirm the diagnosis of ALS but
seldom suggests an alternative diagnosis. Rarely, the needle EMG will
suggest a myopathic process such as
polymyositis or inclusion body myositis. In typical ALS, spontaneous activity
is found at rest in affected regions and
includes fibrillations, positive sharp
waves, and fasciculations. Evaluation
of voluntary motor units usually reveals decreased recruitment of motor
units and increased motor unit firing
rates, greater than 10 Hz. With reinnervation of motor units, patients will
have large-amplitude, long-duration, and
sometimes polyphasic motor units. Selection of muscles for needle examination is an important component of the
EMG. Evaluation of thoracic paraspinal
muscles is particularly useful because
denervation in thoracic paraspinals argues against the alternative diagnosis of
combined cervical and lumber spondylosis mimicking MND. Needle examination of the tongue documents involvement of the disease above the neck,
thereby excluding the possibility of a
cervical cord mass or compression as the
cause of the patients concerns. However, it is often difficult to get good
relaxation of the tongue, and the inexperienced electromyographer may
mistake the small motor units of the
tongue for fibrillation potentials. Needle
examination of facial muscles also may

be used to document the disease of


the bulbar region.
Most ALS specialists require evidence of denervation (LMN dysfunction) on the needle examination in at
least two of the following regions:
brainstem (bulbar/cranial motor neurons) or cervical, thoracic, or lumbosacral spinal cord. For the cervical and
lumbosacral regions, it is suggested
that at least two muscles with different
nerve root and different peripheral
nerve innervations must show EMG
changes. For the brainstem and thoracic region, it is sufficient to demonstrate the EMG change in only one
muscle (tongue, facial, jaw muscles for
the brainstem; paraspinal or abdominal for the thoracic) (Brooks et al,
2000; Ross et al, 1998).
Other laboratory studies that may
support the diagnosis of ALS include
MRI and muscle biopsy. Many patients
have an imaging procedure, usually an
MRI scan of the brain, cervical spinal
cord, or both, to look for evidence of a
tumor, syrinx, herniated cervical spinal
disk, cervical spondylosis with spinal
cord compression, or some other degenerative disease. Cervical MRI is
particularly important if the patient
has no bulbar symptoms or signs. In a
patient with bulbar and spinal symptoms and signs as well as EMG abnormalities in these regions, an MRI is
probably not needed. Although MRI
scans of the brain and spinal cord are
often normal in ALS, they rarely may
show degeneration of corticospinal
tracts. MRI scans are primarily important to exclude alternative etiologies for
the patients clinical presentation.
A muscle biopsy may be useful if
there is suspicion of a myopathy based
on clinical or EMG findings, but it is not
necessary in most cases of ALS. If minimal evidence for LMN involvement is
present, a muscle biopsy that indicates
active denervation, with darkly stained,
small, angular fibers on oxidative and

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.

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

117

" MOTOR NEURON DISORDERS

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:

Divergent views are still held in regard


to so-called primary lateral sclerosis,
the spastic spinal paralysis of Erb.
Some consider it belongs to a separate class from Charcots disease
[ALS], taking presence or absence of
muscular atrophy for the criterion;
but since pure atonic atrophy often
co-exists with slight pyramidal lesions only disclosed after death,
spasticity without wasting might well
represent the opposite extreme of
the same condition.
Renewed interest in PLS was stimulated by Fishers 1977 report of six cases
of chronic progressive quadriparesis.
In 1992, Pringle and colleagues described eight cases with one autopsy
and proposed diagnostic criteria, broadened to include patients with limited
electrophysiologic evidence of denervation. A number of relatively large series
followed. In 2001, Le Forestier and
colleagues reported 20 patients from
the ALS Center at the Salpe
trie`re
Hospital; they contended that most
patients with a diagnosis of PLS show
mild signs of LMN denervation on
follow-up. Cohorts of 25 patients were
described by Zhai and colleagues (2003)
at the NIH and by Singer and colleagues
(2005) from the University of Texas.
Singer and colleagues (2007) recently
summarized their experience in a review article and proposed new diagnostic criteria.
Clinical Features
The most common manifestations of
PLS are leg weakness and spasticity and
spastic bulbar weakness. As with ALS,
sensory symptoms and signs should
prompt continued investigation for an
alternative diagnosis. Although upper
extremity symptoms frequently develop
over time, they are uncommon as an
initial manifestation. Rarely, patients
experience progressive hemiparesis
before spread to the opposite side
becomes clinically apparent.

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

With lower-limb onset, symptoms


usually begin unilaterally. Spasticity produces most of the limb dysfunction in
the early stages, unlike ALS, in which
weakness usually predominates. Patients with PLS typically report stiffness,
clumsiness, or poor coordination as
the initial limb symptom; when limb
weakness occurs, it generally follows
a UMN pattern. Bulbar symptoms 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.
Worsening dysarthria may necessitate
feeding-tube placement, even in the
absence of significant limb involvement.
Emotional lability (pseudobulbar affect)
is common, occurring in more than 50%
of patients.
Although Erbs triad of spasticity,
hyperreflexia, and mild weakness remains the most prominent manifestation of PLS, several other features have
been noted consistently in patients with
PLS. These features include eye movement abnormalities, urinary dysfunction, and cognitive impairment. Patients
do not report visual symptoms, but
abnormalities of eye movements, particularly saccadic breakdown of smooth
pursuits, may be noted on examination.
Urinary concerns initially were considered to indicate a different disease
process. However, most clinical series
now have reported urinary urgency or
incontinence as a frequent symptom,
usually developing several years after
initial presentation. Such symptoms
appear more commonly in PLS than
in ALS.
In most early studies, cognition was
reported as normal in patients with
PLS. However, in recent years, a frontal lobe dementia syndrome has been
reported in PLS patients. These observations, consistent with the finding of
frontal lobe dementia in 10% to 20%
of patients with ALS, have contributed

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.

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

119

" MOTOR NEURON DISORDERS

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

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

careful history and examination. Although PLS generally has been a


diagnosis of exclusion, the same consideration applies to most sporadic
degenerative conditions for which
no diagnostic test is available. Studies
recommended to exclude other diagnoses include serum chemistries, cobalamin (vitamin B12) and copper levels,
as well as serum testing for syphilis,
Lyme disease, and human T-cell lymphotropic virus type 1. Examination of
CSF and imaging of brain and spinal
cord are obtained to exclude compressive lesions or hyperintense lesions suggestive of multiple sclerosis. Imaging
also will exclude compressive lesions
due to a mass or developmental disorder. For patients with limb onset, testing for genetic mutations associated
with hereditary spastic paraparesis
should be considered and be mandatory
if other family members have a similar
disorder. Determination of very longchain fatty acids for adrenomyeloneuropathy and HIV serologies are obtained
when clinically appropriate. All patients
should undergo EMG and NCS. Further
testing, such as evoked potentials and
muscle biopsy, should be performed
according to the clinical situation. Serum CK results are not reported frequently in PLS (Singer et al, 2005) but,
when mildly elevated, support additional LMN involvement.
The hereditary spastic paraplegias
(HSPs) and familial ALS merit particular consideration. The inherited forms
of spasticity originally were termed
hereditary PLS by Erb and later referred
to as Stru
mpell disease (an autosomal
dominant form of HSP now designated
spastic paraplegia type 3) (Holmes
and Shaywitz, 1977). The past decade
has witnessed rapid progress in clarifying the genetic basis for several forms
of HSP. HSP can be autosomal dominant, recessive, or X-linked. Twenty
genetic loci (spastic gait loci [SPG])
have been identified thus far (Fink,

2003; Fink and Ranier, 2004). The most


common form, accounting for 40% of
autosomal dominant cases, is associated with mutation of the SPG4
gene, which produces the protein
spastin. Other autosomal dominant
forms are caused by mutations of the
genes encoding atlastin (SPG3), kinesin
heavy chain (SPG10), nonimprinted
in Prader-Willi/Angelman syndrome 1
(NIPA1) (SPG6), and heat shock protein 60 (SPG13). Autosomal recessive
inheritance has been linked to mutations in paraplegin (SPG7) and spartin (SPG20), and X-linked forms to
L1 cell adhesion molecule (SPG1)
and proteolipid protein (SPG2). Currently, genetic testing is available commercially for spastin, atlastin, and
NIPA1 mutations.
HSP usually presents before 20 to
30 years of age, most commonly in
adolescence. There is some range in
the age of onset of illness, including
patients diagnosed in middle age with
symmetric leg spasticity. Although lower
extremity spasticity generally progresses in severity, arm involvement is
uncommon and bulbar manifestations
are extremely rare (McDermott et al,
2000). Interestingly, LMN dysfunction has
been reported in a subgroup of patients
with mutation of SPG4 (McDermott
et al, 2006). Bladder symptoms are common, and some patients may exhibit
mild sensory loss in the feet, suggesting
posterior column involvement. It is certainly possible that some reported patients with PLS actually had a form of
HSP, although the absence of family
history, typical onset in middle age or
later life, and bulbar involvement would
make this prospect less likely.
In familial ALS, patients usually display
overt UMN and LMN involvement. Rare
cases of PLS have been reported, however, in families with nonsuperoxide
dismutase 1 autosomal dominant ALS
(Brugman et al, 2005) and spinal muscular atrophy type IV (Appelbaum et al,

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.

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

121

" MOTOR NEURON DISORDERS

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,

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TABLE 5-2

"

Proposed Diagnostic Criteria for Primary


Lateral Sclerosis

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

continued on next page

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

123

" MOTOR NEURON DISORDERS

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

"

Classification of Primary Lateral Sclerosis


Clinical primary lateral sclerosis
Fulfills above clinical and laboratory inclusionary and exclusionary features
Suspected primary lateral sclerosis
Fulfills above clinical and laboratory inclusionary and exclusionary
features with the following exceptions:
Four years duration or less
EMG evidence of minimal denervation that does not satisfy El
Escorial criteria for ALS
Complicated PLS (PLS plus)
Patients who fulfill the criteria for clinical PLS or suspected PLS who
also have evidence of dementia, parkinsonism, or sensory abnormalities
(Note: consider multiple system atrophy)

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

features that can be found in such


patients on imaging, transcranial magnetic stimulation, or autopsy. Other
clinicians tell such patients that they
do not at that time meet criteria for ALS
and are, instead, diagnosed with PMA.
Another semantic issue involves the
terms PMA and spinal muscular atrophy
(SMA). Some physicians use the term
SMA synonymously with PMA. Many
clinicians reserve the term SMA for
patients with a genetic disorder of
LMN. It is occasionally difficult to know
with certainty the cause of a particular

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TABLE 5-3

Comparison of Lower Motor Neuron Disorders to ALS


Progressive Spinal
Muscular
Muscular Kennedy
Atrophy
Atrophy Disease

Brachial
Monomelic Amyotrophic
Amyotrophy Diplegia

Age of Onset 3060


(Years)

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

Upper Motor Present


Neuron Signs

Absent

Absent

Absent

Absent

Absent

Lower Motor Present


Neuron Signs

Present

Present

Present

Present

Present

AR (SMN
gene)

XR
(CAG
repeats)

Sporadic

Sporadic

ALS

Inheritance

Sporadic (95%) Sporadic


Inherited (5%)
AD, AR, XR

Distinct
Features

Gynecomastia, Male
predominance
diabetes,
impotence,
infertility

Preservation
of respiratory
and bulbar
function

AD = autosomal dominant, AR = autosomal recessive, XR = X-linked recessive; CAG = cytosine-adenine-guanine


nucleotidase.

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).

Progressive Muscular Atrophy


PMA (also sometimes referred to as
Aran-Duchenne syndrome) comprises
approximately 10% of patients with
MND (Van Den Berg-Vos, et al, 2003).
It is slightly more common in men, with
an earlier mean age of onset than ALS.
Patients receiving the diagnosis of PMA
represent a mixed group, including
patients who have ALS but lack clinical
features of UMN involvement as well as
patients with a purely LMN disorder.
Therefore, it is impossible to know for
certain the clinical course and prognosis
of PMA. As a group, patients with PMA
have a much better prognosis than
Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

125

" MOTOR NEURON DISORDERS

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.

those with ALS. In one series, patients


with PMA showed a 5-year survival rate
of 56% (Chio
` et al, 1985).
Spinal Muscular Atrophy
SMA is a diverse group of hereditary
MNDs, selectively involving LMNs, particularly the anterior horn cells of the
spinal cord. Adult-onset SMA, referred
to as type IV, has several forms and
usually begins after the age of 20. The
prevalence is estimated to be 0.32 per
100,000 population and accounts for
less than 10% of all SMA cases. Weakness is usually greater in the legs than in
the arms. The most common inheritance pattern (seen in approximately
two-thirds of patients) is autosomal
recessive, with a mean age of onset in
the fourth decade (Rudnik-Scho
neborn
et al, 1994). The autosomal dominant
form accounts for one-third of cases
and shares a similar clinical phenotype
(Pearn, 1978). The adult-onset disease
is slowly progressive, with only a
small proportion of patients becoming
wheelchair dependent after 20 years.
Patients typically present with symmetric proximal or generalized weakness
and fasciculations. SMA rarely affects
bulbar muscles, and respiratory muscles
generally remain unaffected. UMN signs
are absent. Other forms of SMA can
involve predominantly distal muscles
(so-called distal SMA) (Harding and
Thomas, 1980). Distal SMA also can be
either autosomal recessive (two-thirds)
or autosomal dominant (one-third).
Most cases of SMA types I, II, III, and IV
are caused by deletions in the survival motor neuron gene on chromosome 5, although the younger the age
of diagnosis, the more likely this mutation will be found (Brahe et al, 1995).
X-Linked Spinobulbar
Neuronopathy
(Kennedy Disease)
Kennedy disease is a form of MND
that is associated with bulbar involve-

ment and X-linked recessive inheritance


(Kennedy et al, 1968). The disease
affects only males, usually beginning
in the third or fourth decade of life.
The initial symptoms include muscle
cramps, a limb-girdle distribution of
muscle weakness, and bulbar symptoms. Distinguishing clinical features
include facial and, particularly, perioral
fasciculations, which are present in
more than 90% of patients, hand tremor,
and tongue atrophy associated with a
longitudinal midline furrow. There is
no evidence of UMN involvement. Although sensory examination is typically
normal, sensory NCS are frequently abnormal. Other systemic manifestations
include gynecomastia in 60% to 90% of
patients due to elevated gonadotropin
levels associated with testicular atrophy,
feminization, impotence, and infertility.
Diabetes mellitus is seen in 10% to 20%
of patients. Genetic testing can be
performed to confirm the presence of
an abnormal trinucleotide-repeat expansion (CAG) in the androgen receptor
gene on the X chromosome (La Spada
et al, 1991). In healthy individuals, the
repeats range from 17 to 26 in this
coding area, whereas, in Kennedy disease, the number of repeats ranges
from 40 to 65. The number of the
enlarged CAG repeat is significantly
correlated with the age of onset but
has no correlation with severity of
weakness, degree of sensory neuropathy, presence of gynecomastia, or impotence (Case 5-3).
Monomelic Amyotrophy
(Focal Motor Neuron Disease,
Hirayama Disease)
Monomelic amyotrophy usually refers
to an MND originally described as
juvenile muscular atrophy of the distal
upper extremity by Hirayama in 1959
in which muscle weakness remains
limited to several myotomes (usually
C5 to T1) within a single extremity

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

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.

(Hirayama et al, 1987). The mean age


of onset is typically 20 to 35 years with
a male predominance (2:1). Patients
demonstrate preferential weakness in
the hand and forearm muscles, which
progresses rapidly over a period of 2
to 3 years and subsequently remains
stable. Approximately 75% of cases involve the upper extremities, and the
others involve the lower extremities.
Reflexes in the involved muscles are

invariably hypoactive or absent. There


are no UMN signs, and sensory symptoms are limited to hypesthesia to
pin and touch in approximately 20% of
patients. In 50% of cases, the weakness remains localized to one limb;
the other 50% of cases show clinical
evidence of involvement in the contralateral limb. Electrodiagnostic studies often show evidence of bilateral
involvement, although weakness may

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.

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

127

" MOTOR NEURON DISORDERS

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.

be clinically apparent in only one extremity (Donofrio, 1994).


MRI may reveal a normal cervical
spinal cord, but bilateral or unilateral
cord atrophy often is seen (Chen et al,
2004). Hirayama and colleagues (2000)
have suggested that this syndrome
may be related to either local compression of the cervical cord or circulatory insufficiency caused by an
anterior shift of the posterior dura
during neck flexion. Sometimes abnormalities may be seen on MRI only
when images are acquired with the
neck in a flexed position (forward
displacement of cervical dural sac)
(Hirayama et al, 2000). Neck flexion
also may produce decreased abnormalities on somatosensory evoked
potentials. A recent report from Taiwan describes a useful finding that can
be seen in cervical spine MRI scans
taken in a neutral, nonflexed position
(Chen et al, 2004). These investigators
found that an increased separation
between the posterior dural sac and
adjacent lamina was a highly sensitive and specific finding in Hirayama
patients. They endorse a pathogenic
theory involving imbalance between
the spinal cord and spinal column that
results in a tight dural sac.
Flail Arm Syndrome
Flail arm syndrome is an MND regional
variant consisting of weakness exclusively confined to the upper extremities. Cases have also been described
under the names of hanging arm
syndrome and neurogenic man in
the barrel. Patients with flail arm syndrome have bilateral upper extremity weakness and atrophy that affects
predominantly the proximal arms and
shoulder girdle. The average age of
onset does not differ from that of ALS,
but, in comparison with ALS, this syndrome is significantly more common
in men (Hu et al, 1998; Katz et al,
1999). Average survival is approxi-

mately 5 years, compared with 3 years


for patients with ALS. Although the
overall survival is longer than for ALS,
some patients presenting with a flail
arm phenotype can go on to develop
a typical ALS course. A flail arm pattern is seen in approximately 10%
of patients with MND, although it
is much more common in those of
African descent (Tomik et al, 2000).
Curiously, these patients do not show
the same prolonged survival as white
patients with the flail arm phenotype
(Tomik et al, 2000).
Within the flail arm clinical phenotype, another significant division can be
made. Among patients with this presentation, if weakness remains confined to
the arms for at least 18 months, no
clinically significant progression outside
of the upper extremities occurs and
survival is quite prolonged. In the series
of Katz and colleagues (1999), after a
mean follow-up of 5.5 years, weakness
remained restricted to the upper extremities in seven of 10 patients. When
present, leg involvement was mild. No
patient lost the ability to ambulate
independently, and none developed
bulbar or respiratory involvement. One
patient had restricted weakness for
greater than 10 years. This clinical presentation has been named brachial
amyotrophic diplegia (Katz et al, 1999).
Patients with brachial amyotrophic diplegia (showing no progression beyond
arms by 18 months) represent approximately 2% of all patients with MND.
There may be an analogous process
in the legs, which has been termed
leg amyotrophic diplegia (Rosenfeld
et al, 2002).
SUMMARY AND CONCLUSIONS
The clinical spectrum of motor neuron
disorders is relatively wide, and, depending on the particular clinical phenotype,
one or more of these disorders may be
considered in the differential diagnosis of sporadic ALS. The distribution of

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

weakness, the degree of UMN versus


LMN involvement, the rate of progression, and the presence of associated
neurologic or systemic signs will determine the differential diagnosis for each

individual patient. Recognition of the


clinical MND phenotypes described in
this chapter is critical in light of the more
favorable prognosis of these disorders
compared with sporadic ALS.

REFERENCES
Appelbaum JS, Roos RP, Salazar-Grueso EF, et al. Intrafamilial heterogeneity in hereditary
motor neuron disease. Neurology 1992;42(8):14881492.
Brahe C, Servidei S, Zappata S, et al. Genetic homogeneity between childhood-onset and
adult-onset autosomal recessive spinal muscular atrophy. Lancet 1995;346(8977):741742.
Brooks BR, Miller RG, Swash M, Munsat TL; World Federation of Neurology Research
Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of
amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord
2000;1(5):293299.
Brooks, BR; World Federation of Neurology Research Group on Neuromuscular Diseases.
El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic
lateral sclerosis. J Neurol Sci 1994;124(suppl):96107.
Brugman F, Wokke JH, Vianney de Jong JM, et al. Primary lateral sclerosis as a phenotypic
manifestation of familial ALS. Neurology 2005;64(10):17781779.
Charcot JM. Lecture XVI: transverse myelitis and spasmodic tabes dorsalis. In: Lectures on
the localization of cerebral and spinal diseases. London: The New Sydenham Society,
1883:299300.
Chen CJ, Hsu HL, Tseng YC, et al. Hirayama flexion myelopathy: neutral-position MR
imaging findingsimportance of loss of attachment. Radiology 2004;231(1):3944.
Chio` A, Brignolio F, Leone M, et al. A survival analysis of 155 cases of progressive muscular
atrophy. Acta Neurol Scand 1985;72(4):407413.
Donofrio PD. AAEM case report #28: monomelic amyotrophy. Muscle Nerve
1994;17(10):11291134.
Dumitru D, Wang Y, Syed K, et al. Isolated bulbar ALS (IBALS): clinical and
electrophysiological features [Abstract]. J Clin Neuromusc Dis 2007;9(3):183.
Eymard-Pierre E, Yamanaka K, Haeussler M, et al. Novel missense mutation in
ALS2 gene results in infantile ascending hereditary spastic paralysis. Ann Neurol
2006;59(6):976980.
Fink JK. The hereditary spastic paraplegias: nine genes and counting. Arch Neurol
2003;60(8):10451049.
Fink JK, Ranier S. Hereditary spastic paraplegia: spastin phenotype and function.
Arch Neurol 2004;61(6):830833.
Fisher CM. Pure spastic paralysis of corticospinal origin. Can J Neurol Sci
1977;4(4):251258.

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

129

" MOTOR NEURON DISORDERS

Gordon PH, Cheng B, Katz IB, et al. The natural history of primary lateral sclerosis.
Neurology 2006;66(5):647653.
Harding AE, Thomas PK. Hereditary distal spinal muscular atrophy: a report on
34 cases and a review of the literature. J Neurol Sci 1980;45(23):337348.
Hirayama K, Tokumaru Y. Cervical dural sac and spinal cord in juvenile muscular
atrophy of distal upper extremity. Neurology 2000;54(10):19221926.
Hirayama K, Tomonaga M, Kitano K, et al. Focal cervical poliopathy causing juvenile
muscular atrophy of distal upper extremity: a pathological study. J Neurol Neurosurg
Psychiatry 1987;50(3):285290.
Holmes GL, Shaywitz BA. Strumpells pure familial spastic paraplegia: case study and
review of the literature. J Neurol Neurosurg Psychiatry 1977;40(10):10031008.
Hu MT, Ellis CM, Al-Chalabi A, et al. Flail arm syndrome: a distinctive variant of
amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 1998;65(6):950951.
Ince PG, Evans J, Knopp M, et al. Corticospinal tract degeneration in the progressive
muscular atrophy variant of ALS. Neurology 2003;60(8):12521258.
Jackson CE, Amato AA, Bryan WW, et al. Primary hyperparathyroidism and ALS:
is there a relation? Neurology 1998;50(6):17951799.
Kalra S, Arnold D. Neuroimaging in amyotrophic lateral sclerosis. Amyotroph Lateral Scler
Other Motor Neuron Disord 2003;4(4):243248.
Katz JS, Wolfe GI, Andersson PB, et al. Brachial amyotrophic diplegia: a slowly progressive
motor neuron disorder. Neurology 1999;53(5):10711076.
Kennedy WR, Alter M, Sung JH. Progressive proximal spinal and bulbar muscular atrophy
of late onset. A sex-linked recessive trait. Neurology 1968;18(7):671680.
Kress JA, Kuhnlein P, Winter P, et al. Novel mutation in the ALS2 gene in juvenile
amyotrophic lateral sclerosis. Ann Neurol 2005;58(5):800803.
La Spada AR, Wilson EM, Lubahn DB, et al. Androgen receptor gene mutations
in X-linked spinal and bulbar muscular atrophy. Nature 1991;352(6330):7779.

130

Le Forestier N, Maisonobe T, Spelle L, et al. Primary lateral sclerosis: further


clarification. J Neurol Sci 2001;185(2):95100.
McDermott C, White K, Bushby K, Shaw P. Hereditary spastic paraparesis: a review
of new developments. J Neurol Neurosurg Psychiatry 2000;69(2):150160.
McDermott CJ, Burness CE, Kirby J, et al; UK and Irish HSP Consortium. Clinical features of
hereditary spastic paraplegia due to spastin mutation. Neurology 2006;67(1):4551.
Mortara P, Chio` A, Rosso MG, et al. Motor neuron disease in the province of
Turin, Italy, 19661980: survival analysis in an unselected population. J Neurol Sci
1984;66(23):165173.
Pearn J. Autosomal dominant spinal muscular atrophy: a clinical and genetic study.
J Neurol Sci 1978;38(2):263275.

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Pringle CE, Hudson AJ, Munoz DG, et al. Primary lateral sclerosis: clinical features,
neuropathology and diagnostic criteria. Brain 1992;115(pt 2):495520.
Rosenfeld J, Chang SW, Jackson CE, et al. Lower extremity amyotrophic diplegia
(LAD): a new clinical entity in the spectrum of motor neuron disease. Neurology
2002;58(suppl 3):411412.
Ross MA, Miller RG, Berchert L, et al; rhCNTF ALS Study Group. Toward earlier diagnosis
of amyotrophic lateral sclerosis: revised criteria. Neurology 1998;50(3):768772.
Rowland LP. How amyotrophic lateral sclerosis got its name: the clinical-pathologic
genius of Jean-Martin Charcot. Arch Neurol 2001;58(3):512515.
Rudnik-Schoneborn S, Rohrig D, Morgan G, et al. Autosomal recessive proximal
spinal muscular atrophy in 101 sibs out of 48 families: clinical picture, influence of
gender, and genetic implications. Am J Med Genet 1994;51(1):7076.
Sach M, Winkler G, Glauche V, et al. Diffusion tensor MRI of early upper motor
neuron involvement in amyotrophic lateral sclerosis. Brain 2004;127(pt 2):340350.
Singer MA, Kojan S, Barohn RJ, et al. Primary lateral sclerosis: clinical and laboratory
features in 25 patients. J Clin Neuromusc Dis 2005;7(1):19.
Singer MA, Statland JM, Wolfe GI, Barohn RJ. Primary lateral sclerosis. Muscle Nerve
2007;35(3):291302.
Tomik B, Nicotra A, Ellis CM, et al. Phenotypic differences between African and
white patients with motor neuron disease: a case-control study. J Neurol Neurosurg
Psychiatry 2000;69(2):251253.
Van Den Berg-Vos RM, Van Den Berg LH, Visser J, et al. The spectrum of lower motor
neuron syndromes. J Neurol 2003;250(11):12791292.
Wilson SAK. Amyotrophic lateral sclerosis. In: Bruce AN, ed. Neurology. Baltimore:
Williams & Wilkins, 1940:10151016.
Zhai P, Pagan F, Statland J, et al. Primary lateral sclerosis: a heterogeneous disorder
composed of different subtypes? Neurology 2003;60(8):12581265.

131

Continuum Lifelong Learning Neurol 2009;15(1)

Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.