Generalized muscle weakness 1

Weakness is decrease in muscle strength and fatigue is failure to maintain the expected
contraction. Weak muscles are always more fatigable than normal muscles. Dysfunction at any level of
the neuraxis as well as systemic diseases can produce weakness and fatigue. Neurological causes of
weakness include disorders affecting the upper motor neuron and lower motor neuron systems. A
generalized distribution of weakness usually implies a diffused process affecting the later.
Components of the lower motor neuron system, or motor unit, include anterior horn cell, motor axon,
neuromuscular junction, and skeletal muscle fibres. In general, neuropathic disorders cause distal limb
weakness while disorders of the neuromuscular junction or muscle cause proximal weakness.

1. Peripheral neuropathies
1.1 Clinical features and investigation findings
Peripheral neuropathy can be classified into 1) polyneuropathies with generalized involvement,
and 2) focal neuropathies, such as traumatic and entrapment neuropathies. (The later group is beyond
the scope of this lecture.)
Most polyneuropathies show characteristic motor, sensory and sometimes autonomic
symptoms and signs. The majority of polyneuropathies share a mixed sensory-motor pattern of
abnormalities. However, for some specific conditions, either pattern, i.e., sensory or motor, may
predominate or be exclusively present. Pure autonomic neuropathy is very rare.
When assessing a patient, 1) motor, 2) sensory, and 3) autonomic symptoms and signs should
be discriminated. This can be done through the standard neurological history taking and examination.
Generally speaking, a polyneuropathy is a symmetrical disorder of peripheral nerves with more sensory
than motor symptoms and signs, affecting the legs more prominently compared with the arms and
distally more than proximally, i.e., a length-dependent pattern.
Motor symptoms and signs include fasciculation, skeletal muscle weakness and atrophy, i.e.,
“lower motor neuron signs”. Fasciculations are spontaneous contraction or twitches of muscle fibres
belonging to the same motor unit that occur with the muscle at rest. Fasciculations point to motor
nerve or neuron dysfunction but their presence is not aetiologic-specific, i.e., can be seen with all
conditions in which the lower motor neurons are affected. They can also occur in normal people after
exercise and during fatigue, especially in the calves and hamstrings. Weakness in polyneuropathy is
usually more evident in distal muscles. Denervated muscles will undergo atrophy. For acute
neuropathies, wasting takes three to ten weeks to become apparent. For slowly evolving or arrested
neuropathies, wasting may be minimal or even absent. A neurogenic process causes atrophy of both
type I and II fibres, whereas type II fibres are affected with muscle inactivity, i.e., “disuse” atrophy.
Sensory symptoms can be divided into negative and positive; the former means sensory loss
(numbness) and the later means sensation in the absence of normal stimulation of receptors (e.g.,
paraesthesia and dysaesthesia). Both are usually present in polyneuropathy but to varying degree
depending on underlying aetiology. Sensory ataxia is another sign of sensory nerve dysfunction
 Generalized muscle weakness 2

although it may also occur with lesions affecting the posterior column. Sensory ataxia results from
impairment of proprioception and is characterized by rombergism, ataxic gait with eye closure,
postural tremor, and pseudo-athetoid movements.
Tendon reflexes need intact afferent and efferent pathways; disturbance of either causes hypo-
or areflexia. Loss of tendon reflexes in polyneuropathies also follows a length-dependent progression.
Autonomic manifestations in polyneuropathies include postural hypotension, cardiac
conduction abnormalities, bladder and bowel disturbance, male erectile dysfunction, alterations of
sweating and other trophic changes of skin.
After establishing the clinical pattern, the time course of the polyneuropathy has to be
determined. Acute polyneuropathy, by definition, reaches the nadir within 4 weeks. Vasculitis causing
nerve infarction might evolve overnight. Subacute polyneuropathy reaches a maximal deficit within 12
weeks. Most polyneuropathies are chronic progressive with impairments increasing over months to
years. Some polyneuropathies run a monophasic course with subsequent arrest of disease progression.
Polyphasic, relapsing-remitting polyneuropathies can occur but are uncommon.

Polyneuropathy has diversed aetiologies. These can be broadly divided into 7 categories:
1) Hereditary,
2) Metabolic,
3) Deficiency,
4) Toxic and iatrogenic,
5) Infectious,
6) Dysimmune,
7) Idiopathic.

The clinical manifestations of different polyneuropathies are usually very similar regardless of
the underlying aetiology. Additional ancillary tests are often needed to distinguish between them.
After careful work-up, a cause can be found in up to 90% of cases.
Clinical Neurophysiology or Electrodiagnostic Medicine is an objective method for assessing
neuronal functions by recording action potentials of excitable tissues. Most routinely performed
procedures are non-invasive. There are two main components of electrodiagnostic studies for testing
the neuromuscular system: 1) Nerve conduction studies for large-fibre functions, and 2) Needle
electromyographic examination for the bioelectric activity of muscles. These tests can define whether
there is a neurogenic process and the extent of disease, discriminate between axonal degeneration and
demyelination, search for subclinical evidence of motor or sensory nerve involvement, measure the
degree of neuronal degeneration, assess neuromuscular junction conduction functions, and assess
disease activity of a myopathic process. Neurophysiological studies detect physiological malfunctions
produced by an underlying lesion rather than directly examine its structural pathology or aetiological
nature. Abnormal electrophysiological findings are, therefore, not pathognomic of specific diseases.
 Generalized muscle weakness 3

The Clinical Neurophysiologist has to define and recognize the pattern of involvement and apply
his/her knowledge to deduce a likely diagnosis or the differentials.
Cerebrospinal fluid analysis is indicated when acquired demyelinating polyneuropathies are
suspected, such as chronic inflammatory demyelinating polyradiculoneuropathy and Guillain-Barré
syndrome. The typical finding is elevated protein in the absence of increased cell counts.
Nerve biopsy is an invasive investigation method; the patient will end up with irreversible
neurological deficits after the procedure. The sural or, less commonly, superficial radial nerve can be
biopsied. A high level of laboratory expertise is essential. Histological examination of the nerve
specimen can demonstrate the presence of neuropathy and the underlying pathological process. The
aim of investigating clinically suspected neuropathies is to look for reversible aetiological factors.
However, there is no specific treatment for many polyneuropathies other than symptomatic therapy.
Clinicians should be aware that the benefit from this harmful investigation is usually limited. Nerve
biopsy is almost always not helpful in advanced neuropathies; histology will demonstrate chronic
axonal degeneration, the terminal event for most neuropathies, regardless of the underlying aetiology.
Nowadays, with the availability of neurophysiological and molecular techniques, nerve biopsies are,
and should be, seldom indicated.

1.2 Aetiologies

1.2-1 Inflammatory neuropathies

Guillain-Barré syndrome is a clinical syndrome characterized by rapidly evolving, relatively
symmetrical flaccid paralysis, areflexia, and laboratory finding of elevated cerebrospinal fluid protein
without cells. The underlying process is an acute polyradiculoneuropathy. Pathological findings in
Guillain-Barré syndrome consist of lymphocytic infiltration and macrophage-mediated demyelination.
Conventionally, the clinical term “Guillain-Barré syndrome” came into use interchangeably with the
pathologic term “acute inflammatory demyelinating polypneuropathy”. This concept has, however,
changed profoundly in the last decade. Guillain-Barré syndrome is now believed to be a diverse
disorder, including both demyelinating and axonal forms.
The annual incidence of Guillain-Barré syndrome is 1-2 per 100,000 population. Antecedent
upper respiratory tract or gastrointestinal infections, in particular Campylobacter jejuni-related, are
present in about 70% of cases. Guillain-Barré syndrome is thought to be a dysimmune reaction to the
preceding infection. An immune response to specific antigens of infectious organisms that is
misdirected against similar epitopes in the host peripheral nervous system is the likely mechanism of
autoimmunity. The most frequent manifestation of Guillain-Barré syndrome is a fairly symmetrical
ascending paralysis evolving over a few days with mild to moderate sensory accompaniment. Cranial
nerves involvement might be present with bilateral facial weakness and ophthalmoplegia. Preservation
of tendon reflexes is against the diagnosis. Muscle ache in the back and thighs and neuritic pain in the
extremities are common. Symptoms usually progress over one to three weeks. Mortality in Guillain-
 Generalized muscle weakness 4

Barré syndrome is 5-10%. The main causes of death are respiratory failure (25-30% of cases) and
autonomic dysfunctions (manifested in 20-30% of cases). Sphincter involvement is uncommon and
occurs in 5-15% of patients as part of autonomic failure. Guillain-Barré syndrome is a monophasic
disease. Clinical improvement usually begins two to four weeks after progression ceases. Good
clinical recovery is expected in 85% of cases.
The mainstays of care for Guillain-Barré syndrome are optimal supportive care and
anticipation and prevention of complications. It is essential to monitor the respiratory and
haemodynamic status very closely. Regular observation of the vital signs, forced vital capacity, and
cardiac rhythm is mandatory. This should be supplemented by arterial blood gas analysis to look for
type II respiratory failure if indicated. (In fact, the same applies for all neurological emergencies
causing respiratory muscle weakness.) Intensive care unit admission for close monitoring with or
without mechanical ventilatory support should be considered when there is evidence of respiratory
fatigue or haemodynamic decompensation. The course of Guillain-Barré syndrome can be modified by
immunotherapy including plasmapheresis and high dose intravenous immunoglobulins.
The symptoms of chronic inflammatory demyelinating polyradiculoneuropathy, by definition,
evolve over at least eight weeks. Some cases run a relapsing-remitting course. It is also dysimmune-
mediated and some cases are secondary to an underlying paraproteinaemia such as from
lymphoproliferative diseases or plasma cell dyscrasias. Chronic inflammatory demyelinating
polyradiculopathy is characterized by elevated protein without pleocytosis in cerebrospinal fluid and
finding evidence of demyelination with electrophysiological studies. It is important to recognize this
condition because it may respond to immunotherapy such as corticosteroids, plasmapheresis, and high
dose intravenous immunoglobulins. In appropriate cases, treatment can be directed against the
underlying haematological disorders.

Reference:
Hahn AF. Guillain-Barré syndrome. Lancet 1998;352:635-41.
Asbury AK. New concepts of Guillain-Barré syndrome. J Child Neurol 2000;15:183-91.
Chan KH, Cheung RTF. Guillain-Barré syndrome. Medical Progress 2002;29(3):13-8.

1.2-2 Hereditary neuropathies

Charcot-Marie-Tooth disease or hereditary motor and sensory neuropathy is a group of
familial diseases characterized by early-onset slowly progressive polyneuropathy, typically associated
with pes cavus and marked distal wasting (inverted champagne bottle-shaped lower limbs). The
clinical severity depends on the subtype of disease but most patients have normal lifespan. Commoner
syndromes include hereditary motor and sensory neuropathy type I (demyelinating), type II (axonal),
and X-linked, Dejerine-Sottas disease, and hereditary neuropathy with liability to pressure palsy.
There is considerable genetic heterogeneity; different genotypes can share the same phenotype and the
 Generalized muscle weakness 5

same genotype can be expressed in different phenotypes. Most of the hereditary motor and sensory
neuropathies are of autosomal dominant inheritance. The prevalence is 5 per 100,000 population.
Spinal muscular atrophy is a group of inherited diseases affecting only the lower motor neuron
system. Onset is usually in infancy or childhood. Prognosis is variable depending on the subtype of
disease; death from respiratory failure can occur from early childhood to middle age. The adult onset
form runs a more benign course and can be compatible with normal life-span.

1.2-3 Motor neuron disease

Motor neuron disease is a progressive degenerative disease affecting both the corticospinal
tract neurons and anterior horn cells resulting in a combination of upper and lower motor neuron signs
in the same patient, hence the other name for motor neuron disease is amyotrophic lateral sclerosis
(amyotrophy – lower motor neuron, lateral sclerosis – upper motor neuron). The annual incidence is 1-
2 per 100,000 population (life-time prevalence about 1 in 1,000). The mean age of onset is 60 years.
The cause of motor neuron disease is unknown. Although a genetic aetiology is advocated,
only a minority of cases could be attributed to known genetic defects – 5-10% of patients have a
positive family history suggestive of autosomal dominant trait, 20% of which have mutations of the
copper-zinc superoxide dismutase (SOD1) gene on chromosome 21. The majority of patients represent
sporadic cases with about 2% of them having SOD1 gene mutations and 1% having neurofilament
heavy chain gene mutations.
Physical findings in motor neuron disease include fasciculations, muscle wasting, weakness,
and brisk tendon jerks with up-going plantar responses, representing the mixed upper and lower motor
neuron involvement. Eye movements and sphincter control are spared until a late stage. As the disease
progresses, there will be bulbar and respiratory muscles involvement. The sensory component is not
affected primarily in motor neuron disease so that the presence of sensory symptoms or signs will cast
doubt on this diagnosis. Neurophysiological findings in motor neuron disease include widespread
motor denervation but preserved sensory responses. The main differentials of motor neuron disease
include cervical myeloradiculopathy (cord + root involvement) and subacute combined degeneration
of cord, in which both upper and lower motor neuron signs are present. Patients with spinal muscular
atrophy have isolated lower but not upper motor neuron features. Discriminating these conditions from
motor neuron disease is not difficult with careful clinical  neurophysiological assessment.
There is no available treatment for motor neuron disease that is of unequivocal benefit to
reverse or halt disease progression. The patient will die from respiratory failure or pulmonary
complications 2-4 years after disease onset. Prior to the terminal phase, particular attention should be
given to nutritional care and physical therapy to prevent complications from immobility. Psychological
support to the patient and family is also important. Assisted ventilation with permanent tracheostomy
and mechanical ventilator can prolong survival, as well as the patient’s and his/her carers’ sufferings,
for many years.
 Generalized muscle weakness 6

2. Myopathies

2.1 Clinical features and investigation findings

Clinical features of myopathies vary considerably with the underlying aetiology. Generally
speaking, onset of weakness is usually gradual rather than acute and distribution of weakness is
symmetrical. Proximal limb strength is more impaired and the patient will have difficulties in climbing
stairs, rising from the sitting position and combing hair. Weakness of neck flexors, dysphagia, voice
changes, and respiratory failure may occur if the condition is progressive. Sensation and sphincter
functions are unimpaired. Tendon reflexes are preserved until the late stages of disease. Pain and
cramps occur in inflammatory myopathies.
Investigations in myopathic disorders include measurement of muscle enzymes levels, needle
electromyographic examination, muscle biopsy, and genetic studies. Whether the “muscle enzymes”,
including creatine kinase, myoglobulin, aspartate transaminase, and lactate dehydrogenase, are elevated
or not would depend on the type and severity of the underlying myopathic process. Electromyography
can define the activity, but not aetiology, of a myopathic process. Finally, as myopathy can be
secondary to systemic diseases such as endocrinopathies, looking for these causes is often appropriate.

2.2 Aetiologies
Acquired myopathies include the inflammatory myopathies, those complicating systemic
diseases such as endocrinopathies, and toxic myopathies (or drug-induced). Hereditary myopathies
include the muscular dystrophies, myopathies from inherited metabolic abnormalities, and the
congenital myopathies. Myotonia is defined as disruption of muscle relaxation after contraction. The
myotonic conditions, which are related to ion channel defects, should be categorized separately.

2.2-1 Inflammatory myopathies

These comprise the major group of “treatable” myopathies. Inflammatory myopathies can be
divided into those from known causes such as infections (viral – Coxsackie, Echovirus, influenza,
HIV, bacterial – leptospirosis, parasitic – toxoplasmosis, trichinosis, cysticercosis), drug-induced and
sarcoidosis, and idiopathic inflammatory myopathies from unknown or autoimmune causes. The later
comprise the majority of clinically important inflammatory myopathies.
Idiopathic inflammatory myopathies are characterized by chronic lymphocytic and macrophage
infiltration in muscle tissue. There are three distinctive inflammatory myopathies: polymyositis,
dermatomyositis, and inclusion body myositis. Polymyositis can occur in isolate or be associated with
other autoimmune connective tissue diseases. Incidence peaks from age 40 to 60 and is more frequent
in female. Muscle biopsy shows endomysial infiltration of mononueclear cells and scattered muscle
fibre necrosis. Anti-Jo-1 antibody is found in 20-30% of cases and is associated with interstitial
pneumonitis. Dermatomyositis affects a younger population than polymyositis. Fifteen percent of
adult-onset dermatomyositis is tumour-related, i.e., paraneoplastic, such that investigating for an
underlying malignancy is essential. Dermatomyositis is mediated by humoral factors against capillary
 Generalized muscle weakness 7

endothelial cells resulting in a complement-mediated microangiopathy. Muscle damage is secondary to

ischaemia. Muscle biopsy shows perivascular and perifascicular infiltration, in contrast to polymyositis.
Dermatological manifestations occur in 90% of cases. These include a heliotrope rash (blue-purplish
discolouration) on the upper eyelids with oedema, a flat red rash on the face and upper trunk, and
erythematous induration with violaceous scaly eruption of the knuckles and extensor surface of other
joints. The rash can be photosensitive. Management of polymyositis and dermatomyositis is by
immunosuppression therapy and close clinical monitoring of treatment response. Biochemical
monitoring with creatine kinase is not reliable as the level might not correlate with disease activity.

2.2-2 The muscular dystrophies

Muscular dystrophy is conventionally defined as an inherited myopathy in which weakness is
progressive and there are no histopathological abnormalities other than degeneration and regenertaion,
i.e., no evidence of storage or metabolic disorders. More common or important muscular dystrophy
syndromes include Duchenne muscular dystrophy, Becker muscular dystrophy, facioscapulohumeral
dystrophy, limb-girdle muscular dystrophy and Emery Dreifuss dystrophy. Less common muscular
dystrophies include congenital muscular dystrophy, distal muscular dystrophy, and oculopharyngeal
muscular dystrophy. Myotonic dystrophy was included as one of the muscular dystrophies but it might
be more appropriate to consider it with a different class of disorder.
Duchenne muscular dystrophy and Becker muscular dystrophy are X-linked disorders. The
incidence of Duchenne muscular dystrophy is one in 3,500 live births in Caucasian populations. It
begins to manifest at early childhood with difficulties in running and later climbing stairs. Because of
knee and hip extensor weakness, the boy has to climb up his thighs by pushing down on them in order
to extend his hips and trunk – the Gower’s manoeuvre. Most patients have enlarged calves
(pseudohypertrophy). Weakness continues to progress and the patient typically becomes wheelchair-
dependent at the age of 12. Cardiomyopathy and ECG conduction abnormalities are common.
Intelligence is marginally subnormal but consistently lower than the general population. The creatine
kinase level in Duchenne muscular dystrophy is increased more than 10 times the upper limit of
normal until the late stage. Muscle biopsy, which shows characteristic immunohistological findings,
confirms the diagnosis. Death occurs in the late teens or early 20s from respiratory and cardiac
complications. The clinical manifestations of Becker muscular dystrophy are less severe. The patient
will continue to ambulate beyond age 15 and death is delayed until middle-age. There is an
intermediate variant, denoted “outliers”, in whom the ability to walk is retained after age 12 but not
beyond 15. Mild variants with non-disabling later-onset weakness also occur. Management is
essentially supportive, including splinting and physiotherapy, corrective surgeries, and ventilatory care.
Emery Dreifuss dystrophy is an X-linked or autosomal dominant disorder. The patient presents
early with humeroperoneal wasting with prominent contractures and striking cardiac abnormalities.
Facioscapulohumeral dystrophy is of autosomal dominant inheritance. Disease intensity varies even
 Generalized muscle weakness 8

within the same family. The combination of facial weakness and scapular winging is characteristic.
Onset is usually during adolescence. The prevalence of limb-girdle muscular dystrophy is 1 in 100,000.
The typical presentation is progressive proximal wasting and weakness from childhood. Inheritance
may be dominant or recessive. The clinical presentation might mimic other muscular disorders.
Identification of muscle membrane protein components deficiencies, including dystrophin and
sarcoglycan, enabled classification of some muscular dystrophy syndromes into dystrophinopathies
and sarcoglycanopathies, with the former including Duchenne and Becker muscular dystrophies and
the later some cases of limb-girdle muscular dystrophy. In Duchenne muscular dystrophy, dystrophin
stain shows no or only a few positive fibres. In Becker dystrophy, quantitative method by Western blot
demonstrates partial deficiency or, more often, reduced amounts of smaller molecular weight,
functionally abnormal proteins. Recently, defects involving several membrane protein components
were found in other dystrophies. Despite identification of these defective membrane proteins, the
pathogenesis of muscular dystrophies remains unclarified. Dystrophin and sarcoglycan are
components of the dystrophin-glycoprotein complex, a membrane-associated protein muscle that spans
the muscle sarcolemma. This protein complex is thought to have a key role in maintaining muscle
membrane stability. It is generally believed that its disruption would lead to a cascade of events
resulting in muscle cell damage. Further studies are needed to prove or disprove this hypothesis.
The classification of muscular dystrophies has changed further with the recognition of disease
genes or molecular basis underlying some of these conditions, although this does not necessarily imply
a better understanding of their pathogenic mechanisms and neither has it led to any realistic
therapeutic breakthroughs so far. Nevertheless, the availability of genetic markers has certainly
facilitated a more precise diagnosis of some muscular dystrophies and that clinical syndromes
manifesting with similar phenotypes can be distinguished from each other with greater ease. (This is
only applicable for conditions with genetic markers discovered.) An example is the differentiation of
Becker dystrophy from limb-girdle muscular dystrophy or other resembling conditions like spinal
muscular atrophy, chronic polymyositis and mitochondrial myopathy. Limb-girdle muscular dystrophy
is now known to be a heterogeneous condition encompassing at least 15 different genetic varieties. On
the other hand, Duchenne and Becker dystrophy is now considered the same disease entity at different
ends of a continuous spectrum. A variable size deletion of the dystrophin gene (Xp21) is demonstrated
in most cases of Duchenne and Becker dystrophy. The phenotypic variation depends on whether the
reading frame is disrupted by the mutation or not. Molecular definition of the dystrophin gene has also
helped the identification of heterozygote carriers for prenatal diagnosis.

Reference:
Emery AEH. The muscular dystrophies. Lancet 2002;359:687-95.
Mak W, Ho SL. The impact of molecular biology on clinical neurology. HKMJ 2001;7:40-9. (Section on
muscular dystrophies and the principles of gene therapy)
 Generalized muscle weakness 9

2.2-3 Metabolic myopathies

These include myopathies secondary to inborn errors of metabolism such as glycogen storage
(McArdle’s disease, Tarui’s disease, Pompe’s disease, acid maltase deficiency) and lipid storage
disorders (carnitine deficiency, carnitine palmityl transferase deficiency). Clinical manifestations
include exercise intolerance, cramps, rhabdomyolysis, and progressive weakness. Disorders of the
mitochondrial respiratory chain also cause metabolic myopathy as part of a multisystem disease. Other
related problems include polyneuropathy, encephalopathy, stroke-like episodes, epilepsy, myoclonus,
retinopathy, ophthalmoplegia, deafness, migraine, cerebellar ataxia, cardiomyopathy, renal tubular
defects, endocrinopathies, short stature, lactic acidosis, pancytopenia, intestinal obstruction, etc.
Acquired metabolic myopathies are commonly secondary to endocrinopathies including hyper- and
hypothyroidism, Cushing’s syndrome or steroid use, parathyroid problems, acromegaly, and vitamin D
deficiency. These are usually low-grade and the presentation will be mild proximal weakness only.

2.2-4 Congenital myopathies

These comprise a group of rare developmental neuromuscular disorders that manifest at birth
as infantile hypotnoia. As most of these conditions are non-progressive or only slowly progressive,
congenital myopathies are not classified as muscular dystrophies. Diagnosis relies on histopathology.
About forty different congenital myopathies are identified. More common ones include central core
disease, nemaline or rod myopathy, centronuclear/myotubular myopathy, and congenital fibre type
disproportion.

2.3 Skeletal muscle channelopathies

Ion channels are membrane proteins specifically adapted for transmembrane ion flux regulation.
Disorders of these voltage-gated ion channels commonly affect excitable tissues such as muscle and
nerve, resulting in their paroxysmal dysfunctions.
Myotonia and periodic paralysis are the two main disorders related to skeletal muscle
channelopathies. Despite different clinical manifestations, their underlying pathogenic mechanisms are
basically the same – failure to maintain muscle membrane in the refractory state due to leaky channel.
These are mostly of autosomal dominant inheritance, producing two channel populations at the
skeletal muscle membrane: mutant (leaky) and normal. Depolarization of muscle fibre occurs when the
normal resting potential is disrupted by ion leakage through the mutant channels. When leakage
leading to depolarization is mild (5-10 mV), the normal channels can restore back the resting
membrane potential and the muscle fibre can then be re-activated/depolarized again through the
mutant channels, resulting in repetitive firing and myotonia. With stronger leakage (20-30 mV), the
normal channels will not be capable of restoring the resting potential from the depolarized state. The
muscle fibre then becomes persistently inexcitable, leading to flaccid paralysis. The variable clinical
manifestation and disease severity might be related to the ratio of mutant and normal channels.
Skeletal muscle channelopathies include sodium channel defects: paramyotonia congenita, potassium-
 Generalized muscle weakness 10

sensitive periodic paralysis, and potassium-aggravated myotonia; calcium channel defects:

hypokalaemic periodic paralysis and malignant hyperthermia; chloride channel defects: myotonia
congenital; and possibly myotonic dystrophy and proximal myotonic myopathy in which the underlying
channel defects have not been identified.
Clinical myotonia improves with repeated contractions – the warm-up phenomenon, and may
worsen in the cold or after prolonged rest. Paradoxical myotonia (or paramyotonia) worsens after
repetitive contraction. Common myotonic syndromes include 1) myotonia congenita, 2) paramyotonia
congenita, 3) proximal myotonic myopathy, and 4) myotonic dystrophy. Clinical manifestations of the
first three syndromes are restricted to the skeletal muscles but myotonic dystrophy is a multi-systemic
disease. Myotonic dystrophy is an autosomal dominant condition exhibiting anticipation phenomenon.
The responsible mutation is an unstable expansion of a CTG trinucleotide repeat on the long arm of
chromosome 19. The age of onset and clinical manifestations correlate with the size of the expansion.
The trinucleotide repeat can also enlarge with time, accounting for the mid-life onset and its
progressive course. Despite identification of the underlying genetic defect, the pathogenic mechanism
of myotonic dystrophy is still poorly understood. Clinical features include weakness and wasting of
distal muscles, temporalis, sternomastoid, and facial muscles, ptosis, and frontal balding. Myotonic
dystrophy also involves the heart (conduction problems), respiration (obstructive sleep apnoea,
pulmonary hypoventilation), gastrointestinal system (smooth muscle dysfunction), endocrine glands
(diabetes mellitus, gonadal atrophy, low metabolic rate unrelated to hypothyroidism), central nervous
system (lack of motivation, paranoid personality), eyes (cataract, retinal degeneration), and bone (skull
hyperostosis, air sinus enlargement, small pituitary fossa).

Periodic paralysis is a group of diseases characterized by episodic weakness with hyporeflexia

and sparing bulbar and respiratory function. Attacks can be provoked by rest following exercise. The
primary or familial periodic paralysis syndromes are divided into hypokalaemic and potassium
sensitive forms. Periodic paralysis can be secondary to a number of systemic diseases which produce
aberration of potassium concentration. Thyrotoxicosis can cause a sporadic syndrome closely
resembling primary hypokalaemic periodic paralysis.

2.4 Rhabdomyolysis
Rhabdomyolysis refers to an acute fulminating muscle necrosis from various causes such as
major trauma, convulsion, heat stroke, drug-induced myopathies, infective myopathies, and metabolic
myopathies. It is characterized by widespread muscle pain, weakness and dark urine. Myoglobulinuria
is an early feature (urine dipstick will be +ve for “blood” but microscopy will not review red cells) and
may lead to acute renal failure. Other complications include hyperuricaemia, hyperkalaemia,
hypocalcaemia, hyperphosphataemia, and disseminated intravascular coagulation. Management is by
osmotic and alkaline diuresis to promote excretion of myoglobulin, renal replacement therapy when
indicated, and correction and treating complications of electrolyte abnormalities.
 Generalized muscle weakness 11

3. Neuromuscular junction conduction disorders

Myasthenia gravis is an acquired autoimmune neuromuscular junction disorder of skeletal
muscles. It is associated with autoantibodies that bind to nicotinic acetylcholine receptors at the
postsynaptic membrane. Such antigen-autoantibody interaction leads to dysfunction and destruction of
nicotinic acetylcholine receptors at the neuromuscular junction. The characteristic clinical features are
fatigability and fluctuating weakness of skeletal muscles. Commonly affected muscles are levator
palpebrae, extraocular muscles, followed by bulbar, facial, neck, and limb muscles. In severe
myasthenia gravis, respiratory muscles are involved to cause life-threatening respiratory failure. The
typical presentation is diplopia and ptosis and variable weakness of facial and bulbar musculatures that
worsen towards end of the day. Limb weakness is often relatively mild. Rarely, it causes focal
weakness and atrophy. In Chinese, a mild form of myasthenia gravis affecting only the extraocular
muscles is common, i.e., “ocular myasthenia gravis”. Transient myasthenia in the newborn can follow
placental transfer of maternal acetylcholine-receptor antibodies.
The incidence of myasthenia gravis is approximately 4 per million per year and prevalence is
40 per million. The male to female ratio is 1:2. The usual age of onset is around 30 years. Thymic
hyperplasia is found in over 70% of patients. Thymoma occurs in 15% of patients; 30% of which are
invasive. In general, patients with thymoma have more severe disease and are more likely to be related
to autoimmune diseases. Other associated conditions include autoimmune thyroiditis and adrenalitis,
rheumatoid arthritis and other connective tissue diseases, pernicious anaemia, inflammatory bowel
diseases, haemolytic anaemia, autoimmune thrombocytopenia, aplastic anaemia, primary ovarian
failure, and pemphigus.
Investigations in myasthenia gravis aim at 1) establishing the diagnosis by demonstration of
myasthenia, and 2) identifying associated conditions:
1. Temporary improvement in muscle strength can be produced by intravenous injection of 10
mg of edrophonium (Tensilon® test), a short-acting anticholinesterase, although falsely
negative as well as positive results are not uncommon. Neuromuscular junction conduction
defect can also be demonstrated with neurophysiological techniques, but interpretation by a
competent Clinical Neurophysiologist is mandatory to derive a meaningful conclusion from
these studies. Finally, acetylcholine receptor antibody can be detected in 60-90% of patients
(30-70% of Chinese patients). Myasthenia gravis is a clinical diagnosis. There is no “gold-
standard” confirmatory test for this disorder and findings of the above tests should not be
interpreted in isolation. Integration into the appropriate clinical context is essential. This
concept also applies for many situations in clinical neurology.
2. CT scan of the thorax is indicated in all newly diagnosed myasthenia patients. Clinical 
laboratory evidence for other autoimmune diseases should be looked for.
 Generalized muscle weakness 12

Anticholinesterase inhibits hydrolysis of acetylcholine by acetylcholinesterase at the synaptic

cleft such that acetylcholine can remain and act on the acetylcholine receptors for a more prolonged
duration. Pyridostigmine, a longer-acting anticholinesterases than edrophonium, is commonly used.
Treatment may be associated with cholinergic side-effects, including salivation, diarrhea, intestinal
colic, and muscle fasciculations, which limit higher doses. Additional anti-muscarinic agents, such as
propantheline, may help to counteract these side-effects. Corticosteroid treatment is indicated in
moderate to severe disease or those with inadequate response to anticholinesterase. Thymectomy is
indicated for thymoma and should be considered for patients with generalized symptoms, i.e., not pure
ocular. Thymectomy for the later group gives full recovery in one third and improvement in one half.
Trans-sternal rather than endoscopic thymectomy is needed to ensure complete clearance. Severe,
acute manifestation of myasthenia gravis, i.e., “myasthenic crisis”, responds to plasma exchange.
Optimal supportive care is mandatory before the patient improves with treatment (see section on
Guillain-Barré syndrome). Medications to be avoided in myasthenia patients include aminoglycosides,
D-penicillamine, sedatives, non-depolarizing neuromuscular blocking agents, and some anti-
arrhythmic agents (quinidine, lignocaine, procainamide, -blockers).
Lambert-Eaton myasthenic syndrome is a rare disorder presenting as variable weakness of
proximal muscles, mild ocular involvement, and autonomic involvement, resembling a myopathy.
Limb reflexes are depressed. It is an immune-mediated “pre-synaptic” neuromuscular junction
disorder due to impaired calcium channel mediated acetylecholine release. Early-onset Lambert-Eaton
myasthenic syndrome is an idiopathic autoimmune disorder but late-onset disease is often associated
with small cell lung carcinoma, i.e., a paraneoplastic phenomenon. The responsible autoantibody is
voltage-gated calcium channel antibody. Lambert-Eaton myasthenic syndrome responds to steroid,
plasma exchange, 3,4-diaminopyridine, anticholinesterase, and removal of the underlying tumour.
Botulism is now rare. It follows consumption of an endotoxin produced by Clostridium
boulinum, the heat- and dry-resistant spores of which typically contaminate inadequately preserved
food (e.g., sausages, botulus = sausage in Latin, canned meat or mushrooms). Botulinum toxins bind to
motor nerve terminals, blocking and destroying acetylcholine receptors. Affected patients present with
an acute symmetrical flaccid paralysis with autonomic involvement. There is no specific therapy other
than optimal supportive and ventilatory care while awaiting the motor nerve terminals to regenerate.
Congenital myasthenia is a heterogeneous group of non-immune disorders. Most are recessive
disorders. They are present at birth or early childhood. They are non-progressive and often improve in
adolescence. These include: 1) Pre-synaptic: familial infantile myasthenia, 2) Post-synaptic: congenital
neuromuscular junction acetylcholinesterase deficiency or acetylcholine receptor deficiency.

Meriggioli MN, Sanders DB. Myasthenia gravis: emerging clinical and biological heterogeneity. Lancet
Neurology 2009;8:475-490.
Chan KH, Ho SL. ‘An update on myasthenia gravis.’ The Hong Kong Practitioner 2000;22:8-20.
 Generalized muscle weakness 13

4. Floppy infant syndrome

Student should know the important causes of floppy infant syndrome and how to assess a case.

Key (also applicable to notes on my previous WCS):

Essential reading
Optional reading
(Of course, both can be optional at your own discretion)