Neuromuscular diseases

Prof. Nerija Vaičienė-Magistris

Department of Neurology
2015/2016
 Classification of neuromuscular disorders

I. Diseases of motor neuron (neuronopathies)

II. Diseases of peripheral nerves (neuropathies)

III. Diseases of neuromuscular junction

IV. Muscle diseases

 Frequent features of NMD
• Weakness (restricted, generalized; acute, slowly progressive)
• Impairment of movements
• Impairment of the gait
• Muscle atrophy
• Contractures, deformities
• Fatigability
• Frequent complications (respiratory, nutrition, heart)
• Chronic and progressive
• Genetic
• No pathogenetic treatment, management of complications is
crucial
 Clinical evaluation of NMD
• Muscle strength
• Muscle tone (spasticity, rigidity, hypotonia, myotonia)
• Muscle bulk (atrophy, hypertrophy, pseudohypertrophy)
• Reflexes (absent, diminished, increased; symmetry)
• Fasciculations, cramps, spasms, pain
• Fatigability
• Contractures, deformities
• Sensory involvement
• Evaluation of the gait
• Special clinical testing
• Multidisciplinary testing
 Electrodiagnostic tests

• Electromyography (EMG):
• Fibrillation and fasciculation potentials
• Changes in the size and shape of motor unit potentials
• Electroneurography (ENG) or nerve conduction studies
• Slowing of the nerve conduction velocity (NCV) or block indicates
demyelination
• In axonal lesion NCV slowed only slightly
• Repetitive stimulation studies for neuromuscular junction
transmission
• Transcranial magnetic stimulation (motor evoked
potentials)
• evaluation of central conduction
 Evaluation

• Laboratory tests:
• ↑ creatine kinaze (CK) indicates destruction of muscles
fibers
• Muscle biopsy
• Microscopy
• Electron microscopy
• Histochemical stains
• Molecular DNA testing is available for many NMD
• Diagnosis
• Counseling
 Neuromuscular disorders
I. Diseases of motor neuron
Spinal muscular atrophies
Amyotrophic lateral sclerosis

II. Neuropathies
Hereditary motor and sensory neuropathies

III. Diseases of neuromuscular junction

Myasthenia

IV. Muscle diseases

Duchenne muscular dystrophy
Myotonia
 Neuromuscular disorders
I. Diseases of motor neuron
Spinal muscular atrophies
Amyotrophic lateral sclerosis

II. Neuropathies
Hereditary motor and sensory neuropathies

III. Diseases of neuromuscular junction

Myasthenia

IV. Muscle diseases

Duchenne muscular dystrophy
Myotonia
 Spinal muscular atrophy

• Spinal muscular atrophy (SMA) is neuromuscular disease

characterized by:
• Degeneration of lower motor neurons in the spinal cord and brainstem

• Progressive weakness and atrophy

• A-R inheritance

• Deletion in SMN1 gene (survival motor neuron 1) on 5q14

chromosome which decrease expression of SMN protein. SMN2
gene is present but does not produce sufficient amount of protein.
Normal SMA

Normal SMA
 SMA types
SMA type Age at onset The best achieved Survival
function age

Type I (acute infantile) 0-6 months Never sits <2 years

Type II (chronic 7-18 months Never stands >2 years

infantile)

Type III (chronic >18 months Stands and walks Adult

juvenile)
II-III rd Walks Adult
Type IV (adult onset) decade

SMA – spinal muscular atrophy

 SMA type I, acute infantile form
Werdnig-Hoffman disease
• Symptoms present before 6 months of age.

• They have severe, progressive muscle weakness and

flaccid or reduced muscle tone (hypotonia) - floppy
babies

• Bulbar dysfunction includes poor suck ability, reduced

swallowing, and respiratory failure.

• They have no evidence of cerebral involvement, and

infants appear alert.
 SMA type I, acute infantile form
Werdnig-Hoffman disease
Neurological exam
• Diffuse muscle weakness and hypotonia:
cannot hold their heads up when pulled to
the sitting position; “frog-like “position

• Weakness is greater in proximal than distal

muscles

• Deep tendon reflexes are absent

• In the infant or newborn, fasciculations are

often restricted to the tongue
Werdnig – Hoffman disease
 SMA type I, acute infantile form
Werdnig-Hoffman disease
• Mortality
• The median survival is 7 months, with a mortality rate of 95% by
age 18 months. Respiratory infections account for most deaths.

• Tests
• Detection of deletion in SMN1 gene.

• ENMG – complementary only. Detection of denervation. Difficult to

perform in infants.

• Treatment
• No specific treatment. Prevention and treatment of infections.

• Preclinical and clinical trials.

 SMA type II, chronic infantile form
• Most children present between the ages of 6 and 18 months.
• The most common manifestation is developmental motor delay.
They have difficulties with sitting independently or failure to stand
by 1 year of age.
• Notable symmetric proximal weakness, hypotonia, atrophy of
muscles, and fasciculations.
• Musculoskeletal deformities are prominent, and respiratory failure
can occur.
• The lifespan varies from 2 years to the third decade of life.
Respiratory infections account for most deaths.
 SMA type III, chronic juvenile form
(Kugelberg-Welander disease)
• Appears after age 18 months.
• Slowly progressive proximal weakness. Most children can stand and
walk but have trouble with motor skills, such as going up and down
stairs.
• Patients can ambulate, but they have proximal muscle weakness and
various degrees of muscle wasting.
• The lower extremities are often more severely affected than the upper
extremities.
• Musculoskeletal deformities are prominent.
• Bulbar dysfunction occurs late in the disease.
• The disease progresses slowly, and the overall course is mild. Many
patients have normal life expectancies.
Diagnostic work-up for chronic SMA forms

Tests for differential diagnosis:

• CK is typically normal.
• ENMG –pattern of denervation-reinervation, fibrillation
potentials.
• Genetic testing for mutation in SMN1 gene.
• Muscle biopsy if genetic analysis is unrevealing.
 Medical care
Supportive treatment should be aimed at improving
the patients' quality of life and minimizing disability,
particularly in patients with slow progression.

• A multidisciplinary approach: physical, occupational, speech, and

respiratory therapies
• Prevention of spinal deformities (e.g., scoliosis) and joint
contractures by using physiotherapy, splints, bracing, spinal
orthoses, specialized wheelchairs and seats, and home assistance
devices. Orthopedic surgery.
• Support of family. Societies of patients and families.
• Specific pharmacologic therapy is not available. Clinical trials. (e.g.,
activation of SMN2).
 Neuromuscular disorders
I. Diseases of motor neuron
Spinal muscular atrophies
Amyotrophic lateral sclerosis

II. Neuropathies
Hereditary motor and sensory neuropathies

III. Diseases of neuromuscular junction

Myasthenia

IV. Muscle diseases

Duchenne muscular dystrophy
Myotonia
 Amyotrophic lateral sclerosis (ALS)

Definition

ALS is a progressive disorder characterized by

degeneration of both – upper and lower (peripheral
and central) motor neurons.
 Amyotrophic lateral sclerosis

• Incidence – 1-2 per 100 000

• Peak incidence between 60 and 70 years of age

• Males and females ratio is 1.5:1

• 95% - sporadic cases. 5% inherited as AD disease

 Amyotrophic lateral sclerosis: pathology

• Loss of pyramidal cells of the motor

cortex, associated with degeneration of
corticospinal pathways.
• Anterior horn cell degeneration
• Degeneration of cranial nerve motor
nuclei, particularly of V, VII, X and XII.
• Ventral root atrophy.
• Chronic partial denervation in sceletal
muscle.
 Amyotrophic lateral sclerosis

• Upper motor neuron damage produces weakness,

spasticity and hyper-reflexia

• Lower motor neuron damage results in wasting,

weakness and fasciculations
 Amyotrophic lateral sclerosis

Signs

• Combination of upper and lower motor neuron signs, e.g.,

wasting, spasticity, fasciculations in the limbs.

• Bulbar or pseudo-bulbar (later both) involvement of cranial

nerves. Gag reflex depressed or exaggerated. Fasciculations of
the tongue, later tongue is shrunken, stiff and immobile.

• Progressive involvement of respiratory muscles.

Amyotrophic lateral sclerosis
 Amyotrophic lateral sclerosis

Prognosis

• ALS leads to death within a decade, and in most cases, within

5 years.

• Early bulbar involvement worsens prognosis (dysphagia,

aspiration, pneumonia respiratory insufficiency).
 Amyotrophic lateral sclerosis

ENMG is the most important investigation

– Fasciculation and fibrillation potentials in both upper and
lower limbs
– Reduced number of motor unit action potentials
– Normal motor conduction velocities
– Normal sensory conduction.

• Transcranial magnetic stimulation

– Slowing of central conduction time.
 Amyotrophic lateral sclerosis
Diagnostic criteria:

• Lower motor neuron signs (clinical and/or EMG)

• Upper motor neuron signs
• Progression
• Absent findings include:
Sensory changes
Sphincter disturbances
Visual disturbances
Autonomic dysfunction
Parkinsonism
Dementia of Alzheimer type
Amyotrophic lateral sclerosis: management
The diagnosis needs to be fully and frankly discussed with the
patient as soon as it is established.

• Pharmacotherapy: riluzole, a glutamate antagonist, is the only drug

approved by the FDA for the treatment of ALS. Prolongs survival by
three to six months.

• Symptoms management
• Dysphagia (diet to prevent aspiration, gastrostomy).
• Excess salivation (anticholinergic drugs, BTX-A injection to salivatory
glands).
• Reduction of spasticity (miorelaxants, physical therapy).
• Respiratory failure (tracheostomy with intermittent positive pressure
ventilation).
 Neuromuscular disorders
I. Diseases of motor neuron
Spinal muscular atrophies
Amyotrophic lateral sclerosis

II. Neuropathies
Hereditary motor and sensory neuropathies

III. Diseases of neuromuscular junction

Myasthenia

IV. Muscle diseases

Duchenne muscular dystrophy
Myotonia
Hereditary motor and sensory neuropathies (HMSN)

HMSN – is the group of diseases with different mode

of inheritance and specific genetic mutations. They
are also called Charcot-Marie-Tooth disease.

– HMSN types 1A and B (dominantly inherited hypertrophic neuropathies)

– HMSN type 2 (neuronal type of peroneal muscular atrophy)
– HMSN type 3 (hypertrophic neuropathy of infancy)
– HMSN type 4 (hypertrophic neuropathy associated with phytanic acid
excess)
– HMSN type 5 (associated with spatic paraplegia)
– HMSN type 6 (with optic atrophy)
– HMSN type 7 and others
 HMSN type 1A

• HMSN type 1A is the most common form of hereditary

neuropathy and among the most common inherited
neurologic disorders.

• Incidence - 30/100 000.

• Demyelinating neuropathy.

• Genetics:
– AD inheritance
– Duplication on chromosome 17 (region containing human
peripheral myelin protein 22 [PMP22] gene)
 HMSN type 1A: clinical picture
• The onset is in the 1st – 2nd decade. Because of its insidious onset, some
patients are unaware of their disease or seek medical attention only late
in life.

• Dominating symptoms:
– Distal weakness and muscle atrophy. The legs are more severely and
earlier affected than the arms.
– Hyporeflexia or areflexia is the rule.
– Foot deformities include high arches or flat feet, hammertoes, and
tight Achilles tendons

• Sensation may be normal until adulthood, but mild diffuse sensory loss is
common.

• Patients report tripping over objects because of foot drop. Ankle sprains
and fractures are frequent. Can not walk on heels. Because of
hammertoes and high arches, they have difficulty finding well-fitting shoes
or experience painful calluses.
Foot deformity in Charcot-Marie-Tooth disease
 HMSN type 1A
• The course: slowly progressive disorder. Disability is variable.
Usually patients don’t loose their ambulance. Life expectancy is
normal.

• Electrodiagnostic studies: motor conduction velocity is diffusely

slowed (< than 38 m/s is the cutoff value for HMSN 1).

• Genetic testing: duplication in the region of PMP22 gene on

chromosome 17.

• Medical care: prevention and treatment of deformities

(physiotherapy, foot orthoses, special boots, orthopedic surgery).
No specific pharmacotherapy is available by now.
 Neuromuscular disorders
I. Diseases of motor neuron
Spinal muscular atrophies
Amyotrophic lateral sclerosis

II. Neuropathies
Hereditary motor and sensory neuropathies

III. Diseases of neuromuscular junction

Myasthenia

IV. Muscle diseases

Duchenne muscular dystrophy
Myotonia
 Myasthenia gravis

Myasthenia gravis (MG) is an acquired autoimmune

disorder characterized clinically by weakness of skeletal
muscles and fatigability on exertion.

• Prevalence is 25-40 per 100 000 population.

• Age at onset - characteristic bimodal distribution: 20-30

years (> F), 60-70 years (> M). 10 % starts before 20.
 Pathophysiology of MG
• The antibodies (AB) are directed toward the acetylcholine receptors
(AChRs) at the postsynaptic membrane of neuromuscular junction.
• Binding of AB results in destruction of junctional folds of the
postsynaptic membrane with resultant decreased availability and
number of AChRs and blocking the binding of ACh to AChR.
 Pathophysiology and pathology of MG

• 80-90% of patients with generalized and 50% of ocular

mysthenia have AChRs antibodies.

• The thymus plays the role in pathogenesis being the central

organ in T cell–mediated immunity.
• Thymic hyperplasia is found in most young-onset patients.
• Thymomas occur in 10-15% of MG patients.
 MG: clinical presentation

• Extraocular and eyelid muscle weakness is present initially in

50% of patients and occurs during the course of illness in 90%
as ptosis and/or diplopia. Very often symptoms are asymmetric.

External ophtalmoplegia on the right

 MG: clinical presentation
• Oropharyngeal muscles weakness produces regurgitation of food and
liquids, chocking, aspiration, nasal voice (dysphagia, dysphonia).

• Bilateral facial and jaw muscle weakness – mask like face, difficulty
chewing.

• May affect limbs and axial muscles (especially neck) as well as respiratory
muscles.

• Fluctuating weakness is increased by exertion, during the day and

improves with rest. Presentation and progression vary.

• About 80% patients develop generalized MG, in 20% remains ocular only.
Myashenia gravis: severe ptosis and facial weakness
 MG: investigation
• Pharmacological testing with short –acting cholinesterase inhibitor
(Endrophonium test). Test is positive if muscle strength improves
subjectively and objectively for 4-5 min. (in 90% pts with MG).
• Detection of AChRs antibodies.
• Electrophysiological testing:
– Repetitive nerve stimulation produces an abnormal decrement in the
amplitude over 10%
– Single fiber EMG is the most sensitive test diagnosing MG (technically
more difficult and much more dependent on the experience and skill
of the testing physician).
• Chest CT for detection of thymic abnormalities (thymoma or
hyperplasia)
Repetitive nerve stimulation at 2-3 Hz produces an abnormal
decrement in the amplitude of the evoked potential from the
muscle in patient with myasthenia gravis
 Treatment of MG: principles

• Acetilcholinesterase inhibitors
– Pyridostigmine bromide Usually in combination
– Neostigmine
• Corticosteroids
• Other immunosupresants
– Azathioprine
– Cyclosporibe A, etc.
• Plasmapheresis for exacerbations
• Intravenous immunoglobulin for exacerbations
• Thymectomy
 Emergency in MG

• Myasthenic crisis – respiratory failure due to the weakness of

respiratory muscles requiring ventilation. May be provoked by
intercurrent illness, some medications.
Immediate ventilation. Plasmapheresis – 1st choice treatment.

• Cholinergic crisis results from too high dose of cholinesterase

inhibitors and overstimulation of NMJ due to an excess of ACh.
It leads to flaccid paralysis, respiratory failure, increased
salivation and bronchial secretion.
Immediate ventilation, stop of cholinesterase inhibitors,
atropine.
 Neuromuscular disorders
I. Diseases of motor neuron
Spinal muscular atrophies
Amyotrophic lateral sclerosis

II. Neuropathies
Hereditary motor and sensory neuropathies

III. Diseases of neuromuscular junction

Myasthenia

IV. Muscle diseases

Duchenne muscular dystrophy
Myotonia
 Primary muscles diseases

• Muscular dystrophies
• Metabolic myopathies
• Endocrine myopathies
• Alcohol myopathy
• Mitochondrial myopathies
• Inflammatory myopathies
• Parasitic muscle disease
 Duchenne’s muscular dystrophy (DMD)
• The most common form of muscular dystrophy.

• Affects 1 in 3500 boys born worldwide.

• X-linked inheritance pattern. 1/3 of cases are sporadic.

 Duchenne’s muscular dystrophy (DMD)

• Gene (so called dystrophin gene)

is located at Xp21 chromosome
and encodes protein dystrophin.
• Dystrophin protein is integral to
the structural stability of the
myofiber. Without dystrophin,
muscles are susceptible to
mechanical injury and undergo
repeated cycles of necrosis and
regeneration.
 DMD: clinical signs

• Manifests at the age of 3-7 years with the development of weakness of

the shoulder and pelvic girdle muscles.

• Characteristic waddle gait and lordosis associated with difficulty in

climbing stairs, raising from the chair, floor. Toe-walking is typical early
sign.

• A characteristic manoeuvre (Gowers’ sign) is used to raise from a supine

position.

• The calf pseudohypertrophy are caused by fatty and fibrotic infiltration of

degenerated muscles.

• Development of cardiomyopathy (dystrophin is present in the cardiac

muscle).
Gowers’ sign: the mode of rising from the ground
Calf muscle pseudohypertrophy in DMD
 DMD: development and prognosis
• Muscle weakness and atrophy progresses to all muscle groups involving
distal, neck and respiratory muscles.

• Ambulatory till 10-12 years of age, later – wheelchair bounded.

• Further progression of contractures and scoliosis especially when more

wheelchair dependent.

• Development of symptoms of nocturnal hypoxemia such as lethargy,

headache.

• Development of terminal respiratory or cardiac failure. Survival depends

on ventilation and cardiovascular care (average survival 25 years if on
ventilation).
Development of symptoms in DMD
 DMD: investigations
• Creatine kinase (CK) is elevated to levels that are 20-50 times the
reference range, particularly in the early stages.
• EMG shows myopathic changes and excludes primarily neurogenic
process.
• DNA testing - detection of deletion in the dystrophin gene (positive
in 50-70% cases). Prenatal diagnosis. Detection of carriers.
• Muscle biopsy – supplementary test if DNA testing is negative.
Histology – evidence of muscle necrosis and infiltration by fat and
connective tissue. Immunohistochemical staining – absense of
dystrophin.

• Monitoring of cardiac function

• Monitoring of respiratory function
 DMD: medical care

• No cure yet exists. Research in gene and cellular therapy is

promising.

• Comprehensive multidisciplinary care is aimed to increase

quality of life and prolong lifespan.

Two periods of care:

1. Prolongation of ambulation
2. Care after loosing ambulation (wheelchair dependence)
Multidisciplinary management od DMD patients
 DMD medical care: prolongation of ambulation
• Corticosteroids are the only medication that been found to be favorably
associated with 2-3 years more of independent ambulation, reduced or
delayed need for scoliosis surgery, reduced or stabilized ventricular
dysfunction, and improved respiratory function.
Problems: weight gain, osteoporosis.

• Physical therapy, gentle sports, joint stretching.

• Orthopedic care: knee-ankle-foot orthoses to maintain ability to stand;

tendon release surgery.
 DMD medical care: later stages
Periodical evaluation and management.

• Customized chair, adaptive devices.

• Scoliosis surgery.
• Cardiac management.
• Gastrointestinal and nutrition management.
• Pulmonary management - prevention, non invasive and
invasive ventilatory support.
• Pshychosocial support.
• Pallative care.
 Neuromuscular disorders
I. Diseases of motor neuron
Spinal muscular atrophies
Amyotrophic lateral sclerosis

II. Neuropathies
Hereditary motor and sensory neuropathies

III. Diseases of neuromuscular junction

Myasthenia

IV. Muscle diseases

Duchenne muscular dystrophy
Myotonia
 Hereditary myotonias

• Myotonia is disorder that affects muscle relaxation and causes

stiffness.
• The disorder is caused by mutation in a chloride channel gene
responsible for shutting off electrical excitation in the
muscles, causing muscle fiber membranes to have an
unusually exaggerated response to stimulation
(hyperexcitability).

• AD form – Thomsen’s disease

• AR form – Becker’s disease
 Hereditary myotonias

• Disease starts is childhood and persist throughout the life

without progression.
• Stiffness develop after every forceful muscle contraction and
are most pronounced after a period of inactivity, eg.:
– difficult to relax a tight grip
– difficult to get up from a seated position
– difficult to open eyelids after a strong closure
• Repeated contractions of the same muscles alleviate the
stiffness – “warm-up” phenomenon.
• Low temperatures, surprising noises, sudden need to keep the
balance may trigger acute generalized stiffness and even fall.
 Hereditary myotonias

• Tapping a muscle with a reflex hammer produces muscle

contraction that persists for several seconds - percussion
myotonia ( well triggered on thenar, tongue muscles.)
• Muscles are hypertrophied, patients have athletic look.
• Some cases are mild not much interfering with daily activity.
Some cases might be disabling.

• EMG with the needle shows high frequency repetitive

discharges and a characteristic “dive-bomber” sound.
• Treatment: phenytoin, mexiletine, acetazolamide may
alleviate symptoms.
Hereditary myotonia
Have a nice day!