Cambridge University Press
9780521171854 - Neuromuscular Disease: A Case-Based Approach - By John H. J. WokkePieter A. van DoornJessica E. HoogendijkMarianne de Visser
Excerpt

Introduction: approach to the patient

Introduction

Clinical features, rate of progression, and functional impairment of neuromuscular diseases vary between patients and diseases, even in diseases and within families with the same genetic cause. Acquired neuromuscular disease may also show great variability of symptoms and signs, progression, and response to treatment.

Yet, with a keen clinical eye and sound clinical reasoning, it is possible to establish a clinical and differential diagnosis, and to select relevant ancillary tests. In each following section, we discuss common symptoms and signs.

Time course at onset (Table 1)

“Acute” in neuromuscular disorders reflects a nadir within four weeks after onset. Initial symptoms may be in the remote past. Most hereditary diseases first manifest in childhood or adolescence, but onset at an advanced age is no exception. It is useful to ask when motor milestones were reached and whether the patient could keep up with peers at sports. A common finding in clinical neurology is that many patients with chronic disease will – due to memory activation – on returning from the first visit, recall an earlier onset of manifestations.

Table 1. Time course of neuromuscular diseases

• Acute

Nadir within 4 wk after onset

• Subacute

Progressive course lasting a maximum of 8 wk

• Chronic progressive

Progression continuing after 8 wk

• Monophasic

One single disease period

• Relapsing and remitting

Periods of worsening and improvement

Symptoms and signs of the motor system

Fatigue

Fatigue is a common initial complaint of patients with a neuromuscular disease. Examples are amyotrophic lateral sclerosis (ALS), Pompe disease, and myotonic dystrophy (DM). Fatigue may be a late or residual symptom as in patients with postpoliomyelitis syndrome, Guillain–Barré syndrome (GBS), and myositis. If fatigue is the predominant feature, without objective signs such as weakness or elevated serum creatine kinase (CK) activity, it is unlikely to be a neuromuscular disease. Chronic fatigue syndrome is not a neuromuscular disease.

Cramps

Cramps – spontaneous, short-lasting, and painful contractions of part of a muscle – can be stopped by stretching the muscle. Cramps occur in healthy individuals during and after exercise or sports, and when asleep. The muscles affected most frequently include the calves, knee flexors, and foot muscles. Tongue muscles may cramp after yawning.

Disorders of lower motor neuron cells (LMN) and motor neuropathies may cause cramps of all afflicted muscles. These pathological cramps do not occur in pure pyramidal or corticobulbar lesions. Cramps may occur in various myopathies (Table 2).

There is no evidence-based treatment for muscle cramps. Quinine derivates can be considered in individual cases but side effects must be taken into account.

Myotonia

Myotonia is sustained contraction and delayed relaxation of skeletal muscle caused by repetitive waxing and waning discharges of the muscle membrane. These give a characteristic electromyography (EMG) sound resembling a motorbike being started, previously called “dive bomber sound”. Myotonia originates

Table 2. Myopathies with cramps and cramp-like symptoms

Muscle cramps can also occur:

from the muscle and – in contrast to muscle cramps – occurs spontaneously without stimulation of the muscle through a nerve action potential. Action myotonia (Video 1) is slow relaxation of a muscle after voluntary contraction. Percussion myotonia occurs after mechanical stimulation of a muscle with a reflex hammer. Patients may complain of loss of relaxation when shaking hands, after grasping objects, or when playing the piano or organ. Repeated contraction decreases myotonia in DM types 1 and 2. Increased myotonia after repeated contractions and cold-induced myotonia are features of paramyotonia congenita.

Pain in neuromuscular diseases

Neuropathic pain must be distinguished from musculoskeletal pain resulting from contractures, overuse, or inflammation. Neuropathic pain can be localized in the area of an affected nerve or nerve root and may be more often present at rest, especially at night. Neuropathic pain and other exteroceptive system symptoms usually occur in diabetic, alcoholic, and amyloid neuropathy. Acute radicular pain is a feature of Lyme radiculoneuritis. Various types of pain can be present in or even precede weakness in GBS.

Muscle pain at rest may occur in dermatomyositis, polymyositis, viral myositis, and rhabdomyolysis. Stiffness can be an accompanying feature. Pain during exercise occurs in McArdle disease. Muscle pain can also be found in muscular dystrophies; for example, facioscapulohumeral dystrophy (FSHD), Becker muscular dystrophy (BMD), and limb girdle muscular dystrophy (LGMD) type 2I.

Fasciculations and myokymia

“Muscle twitches,” or fasciculations, are spontaneous simultaneous contractions of all muscle fibers belonging to a single motor unit. The number of muscle fibers per motor unit varies from six in the thenar muscle to 600 in the gastrocnemius muscle. As a consequence, the type of fasciculation can vary between fine and coarse. Fasciculations do not result in coordinated movement of a muscle. Sometimes patients with fasciculations complain of restlessness in the muscles or of a feeling of ants creeping under the skin, but usually fasciculations pass unnoticed. To interpret fasciculations, the muscle must be examined at rest. Fasciculations can increase following strenuous contraction or after tapping the muscle. In healthy individuals, fasciculations may occur in various muscles including the calves and knee flexors following strenuous exercise and sports (Video 2). Treatment of myasthenia gravis with pyridostigmine may induce fasciculations (Video 3). Fasciculations together with muscle cramps may be a harbinger of motor neuron disease (MND)/ALS, or be an innocent but sometimes incapacitating affliction (Table 3).

Diseases that affect peripheral innervation may cause fasciculations. Reinnervation will lead to larger motor units and to coarse fasciculations (Video 4). Waves of fasciculations and of myokymia may mimic undulations. Undulating myokymia is a feature of neuromyotonia (Isaac’s syndrome, Morvan’s syndrome; Video 5) and of

Table 3. Neuromuscular disease that may manifest with cramps and fasciculation

rippling muscle disease. Fasciculation is not a feature of myopathy.

Myokymia, the term applied to spontaneous rhythmic and transient movements of a few muscle bundles within a muscle, does not cause movement in a joint. Myokymia may occur in healthy persons after strenuous exercise. Well known is myokymia in the orbicularis oculi muscle, which is associated with fatigue. Waves of myokymia are a feature of peripheral nerve hyperexcitability syndrome.

Atrophy and pseudohypertrophy

The volume of a skeletal muscle is determined by genetic predisposition, nutritional state, activity, and exercise. Unfortunately, no clear definitions exist for hypertrophy or atrophy in an individual patient. In severely ill patients and after a period of inactivity, generalized muscle atrophy occurs. Generalized atrophy can even occur after a period of two weeks of bed rest. In these patients, the skeletal muscle biopsy shows type 2 muscle fiber atrophy. Following denervation, atrophy of the corresponding muscle is noted after two weeks (Figure 1). Hypertrophy of the calves can be a residual finding after chronic, long-standing reinnervation in GBS, or S1-radiculopathy (Figure 2), or Charcot–Marie–Tooth (CMT) disease. Hypertrophy of leg muscles is a feature of Becker myotonia. Pseudohypertrophy of the calves due to increase in fat and connective tissue may occur in Duchenne and Becker muscular dystrophies (Figure 3), and in some of the LGMD, including the sarcoglycanopathies, LGMD2C, LGMD2I, and LGMD2L.

Atrophy caused by long-standing functional denervation of the neuromuscular junction that is blocked and destroyed by antibodies, can be a residual feature of myasthenia gravis in remission and in anti-muscle-specific kinase (MuSK) myasthenia gravis. Bulbar muscles are frequently affected (Figure 4). Hypertrophy of the tongue, macroglossia, can occur in hypothyroidism, BMD, Pompe disease, and amyloid myopathy.

Hypotonia and hypertonia

Hypotonia is the loss of resistance during passive movement. Hypertonia is defined as increased resistance during passive movement and results from upper pyramidal tract lesions that cause loss of inhibition. Hypertonia is characterized by a velocity-dependent increase in tonic stretch reflexes with exaggerated reflexes resulting from hyperexcitability. A consequence of hypertonia is the loss of dexterity that can be observed in patients with unilateral or bilateral lesions of the pyramidal tract. Bilateral lesions of the corticobulbar tracts may cause difficulties with tongue movements (Video 6). Some of these patients may even lose the ability to protrude the tongue.

Weakness

Flaccid weakness is the predominant sign of most neuromuscular diseases. Bulbar weakness may cause nasal speech, if the soft palate is weak, or dysarthria, due to weak facial or tongue muscles, or dysphagia. Characteristic facies myopathica may evolve, if all facial muscles are weak. Mild arm or hand weakness is
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Figure 1. Atrophy of the left calf in a patient with S1 radiculopathy (A) becomes more marked as the patient stands on tiptoe (B). In that position – with hands on a desk or against a wall – the calf, biceps femoris, and semitendinosus muscles can be palpated.
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Figure 2. (A) Hypertrophy of the right calf in a patient with S1 radiculopathy. (B) Pseudohypertrophy becomes evident with CT scanning: abnormally thickened gastrocnemius and soleus muscles with areas of lower attenuation compatible with replacement of muscle by fat.
indicated by difficulties with daily tasks such as getting out of a chair, walking up/down stairs, carrying bags, or lifting objects out of cupboards. Mild leg weakness causes buckling of the knees or the tendency to trip. Symptoms resulting from specific weak muscles and corresponding diseases are summarized in Table 4.

For diagnostic purposes, muscle strength is measured using the Medical Research Council (MRC) grading system (Table 5). Manual muscle testing (MMT) using the MRC scale helps to evaluate the disease course and effect of treatment.

Sensory abnormalities

Pain and temperature senses and crude touch are conducted through the somatosensory exteroceptive system (Table 6). The numbers of nociceptors (receptors for pain) vary in different skin areas. Investigation of temperature sensation is indicated only when small nerve fiber neuropathy is suspected. Sensorimotor neuropathy can be part of the spectra of DM and mitochondrial myopathy.

The somatosensory proprioceptive system for tactile sense, vibration sense, and motion and position senses is best examined using a wisp of cotton and the Rydel–Seiffer 128 Hz tuning fork for semiquantitative examination of the vibration sense.

Many patients with impaired proprioception also have a postural and kinetic tremor. A patient with severely impaired proprioception will develop sensory ataxia (Table 7), impaired tandem walking, and a positive Romberg sign. Even instability of the trunk can be observed when the patient comes to sit from a supine position. These patients may report difficulties with performing movements as weakness.

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Figure 3. Hypertrophy of the calves in a patient with Becker muscular dystrophy.
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Figure 4. Atrophy of the edges of the tongue in a patient with classic myasthenia gravis.

Sensation is normal in motor neuron disorders, neuromuscular transmission disorders, and most myopathies.

Reflexes

Hyperreflexia results from hyperexcitability of the muscle stretch reflexes. If there is an abnormality of the muscle stretch – deep – reflexes, the response is manifested by either hypoactivity or hyperactivity; hypoactvity meaning diminution or absence of reflexes. Hyperactivity signifies varying degrees of increased speed and vigor of response, brisk reflexes, exaggeration of the range of movement, decrease in threshold, extension of the reflexogenic zone, and clonus. Hyporeflexia and areflexia result from lesions of part of the reflex arch, the afferent, efferent, or both. Weak skeletal muscles generate reduced or absent reflexes, ALS patients being an exception.

The jaw – masseter – reflex is usually hypoactive or absent, but is hyperactive in bilateral supranuclear lesions, which occur in ALS. Other pseudobulbar reflexes are the corneomandibular, and snout and palmomental reflexes. Elderly patients may have concomitant cerebovascular disease that can explain, through multiple small cerebral infarcts, the occurrence of snout and palmomental reflexes. Pseudobulbar affect – forced laughter, crying, and yawning – may be more reliable pseudobulbar signs.

A Hoffmann sign – opposition and flexion of the thumb and flexion of the index finger when tapping the nail or fingertip of the middle finger – suggests pyramidal tract involvement proximal to C8. The Hoffmann sign is clinically significant if asymmetric or very active.

Two grading systems for muscle tendon reflexes have been widely accepted. First, the Mayo Clinic scale is a nine-point ordinal scale grading reflexes from –4 (absent) to +4 (persistent clonus), 0 being normal. Second, the NINDS myotatic reflex scale grades reflexes from 0 (absent) to 4 (enhanced including clonus). Interobserver agreement on the two scoring systems, however, is poor and a verbal description of reflexes is often more useful. Asymmetry of muscle stretch reflexes and discrepancy between briskness of reflexes between the bulbar region, and arms or legs raise suspicion of a pathological condition. Relatively normal Achilles tendon reflexes with absent knee jerks can be seen in muscular dystrophies.

Superficial abdominal reflexes are frequently intact in corticospinal tract disease. The Babinski sign, the extensor plantar response, represents an inversion of the normal plantar response – plantar flexion of the toes – that is elicited by stimulation of the lateral plantar surface of the foot with a blunt point.

Autonomic functions

History taking identifies complaints of irregular heart action, orthostatic hypotension, increased or decreased

Table 4. Muscle weakness, symptoms, and associated neuromuscular diseases

Muscles affected

Symptoms

Examples of diseases

External ocular muscles

Diplopia, blurred vision

Miller–Fisher syndrome (MFS, Video 8): early

Guillain–Barré syndrome (GBS)

Diabetes mellitus (acute: usually one cranial nerve)

Myasthenia gravis (fluctuating)

Congenital myasthenia gravis

Lambert–Eaton myasthenic syndrome (LEMS): late

Oculopharyngeal muscular dystrophy (OPMD): usually no diplopia perceived by the patient

Myotonic dystrophy (DM) type 1 (ptosis prominent): usually no diplopia perceived by the patient

Mitochondrial cytopathy (often not perceived by the patient due to the chronic progressive nature: chronic progressive external ophthalmoplegia (CPEO); Figure 11)

Eyelid (levator palpebrae muscle)

Ptosis

Functional blindness

Neck pain from increased backward position of the head

Myasthenia gravis (asymmetric); patient may wear sunglasses

LEMS (late)

OPMD

DM type 1

Mitochondrial cytopathy (in early phase, asymmetric)

Pompe disease

Beware that rigid contact lenses may cause ptosis

Muscles for mastication

Slow, impaired mastication

(patient supports the jaw with one hand)

Amyotrophic lateral sclerosis (ALS)

Kennedy disease

Myasthenia gravis

Anti-MuSK myasthenia gravis

OPMD

DM type 1

Congenital myopathy

Facial muscles

Sleeping with eyes open

Loss of facial expression: asymmetry at rest, when speaking or laughing

Hollow temples

Drooling

Difficulty whistling, drinking through straw, blowing up a balloon

Biting on cheeks

GBS

Lyme radiculoneuritis

Myasthenia gravis

Anti-MuSK myasthenia gravis

Congenital myasthenia gravis

Facioscapulohumeral dystrophy (FSHD) (Figure 12)

Congenital myopathy

OPMD

Myotonic dystrophy type 1 (Figure 13)

Proximal myotonic myopathy (PROMM, DM type 2: not as prominent as in DM type 1)

Mitochondrial cytopathy

Muscles for swallowing

Dysphagia

Change of diet

Weight loss (>10% is concerning)

ALS

Progressive muscular atrophy (PMA – late in disease)

Kennedy disease

GBS and MFS

Myasthenia gravis

Anti-MuSK myasthenia gravis

LEMS

OPMD

Sporadic inclusion body myositis (sIBM)

Myositis

DM type 1

Muscles for phonation and articulation

Dysarthria: slurred speech, nasal speech Soft speech: limp, falling, and nonmoving palate

Hoarse speech

ALS

Kennedy disease

Myasthenia gravis

Anti-MuSK myasthenia gravis

OPMD

DM type 1

Charcot–Marie–Tooth (CMT) disease type 2A

Hereditary neuralgic amyotrophy

Tongue

Dysphagia, dysarthria

ALS and PMA

Kennedy disease

Myasthenia gravis

DM type 1

Muscles of the neck

Neck pain

Patients may actively stabilize the head by supporting the chin

Head drop

Difficult head fixation when rising from supine position

ALS and PMA

Myasthenia gravis

Anti-MuSK myasthenia gravis

FSHD

DM type 1

sIBM

Myositis

Idiopathic dropped head syndrome

Muscles of the shoulders and upper arms

Heavy feeling

Difficulty washing hair, brushing teeth

Difficulty taking objects down from shelves

Motor neuron diseases (asymmetry in ALS and PMA)

Spinal muscular atrophy (SMA) types 3 and 4

Myasthenia gravis

Anti-MuSK myasthenia gravis

LEMS

Most muscular dystrophies (asymmetry in FSHD; Figure 14)

Pompe disease

Myositis

Muscles of lower arms and hands

Difficulty writing or using PC, handling objects, fastening buttons

Difficulty carrying shopping bag (finger flexor muscles)

ALS and PMA (asymmetry)

Multifocal motor neuropathy (MMN – asymmetry)

Neuropathies

Distal myopathies

DM type 1

sIBM (deep finger flexor muscles)

Muscles of the pelvis and upper legs

Difficulty rising from chair and from squatting position

Difficulty climbing stairs

Loss of running ability

Waddling gait

ALS and PMA (asymmetry)

Kennedy disease

SMA types 3 and 4

GBS and chronic inflammatory demyelinating polyneuropathy (CIDP)

LEMS

Most muscular dystrophies and other myopathies

In Becker muscular dystrophy (BMD) and IBM the quadriceps femoris muscle can be the first symptomatic muscle

Muscles of the lower legs and feet

Tripping over

Foot drop

Pushing off

ALS and PMA (asymmetric)

MMN (asymmetric)

All motor neuropathies

FSHD (asymmetric)

Distal myopathies

OPMD

DM type 1

Myofibrillar myopathies

Sporadic IBM

Sarcoid myopathy

Paraspinal muscles

Tiredness in the back

Bent spine

Scoliosis

Loss of upright posture

ALS and PMA

FSHD

Central core disease

Myositis

Pompe disease

OPMD

sIBM

Dermatomyositis and polymyositis

Bent spine syndrome

Axial myopathy (Video 9)

Abdominal wall muscles

Drooping abdomen

Pompe disease

FSHD

Respiratory muscles

Dyspnea

Morning headaches

Nightmares

Orthopnea

Postural drop → >10% decrease in forced vital capacity in supine position compared with sitting position

ALS and PMA

SMA type 3

GBS (early)

CIDP (late)

Myasthenia gravis

BMD (late)

FSHD (late)

Myotonic dystrophy

Congenital myopathies

Bethlem myopathy

Pompe disease

Myofibrillar myopathies

Note. Dysarthria due to muscle weakness: nasal speech with weak palate; hollow vowels and consonants (especially “G” and “C”, explosive pronunciation of “P” and “B”). Spastic speech is monotonous and slow.

Table 5. Medical Research Council scale for assessment of muscle strength

Grade 0

No contraction

Grade 1

Flicker or trace of contraction

Grade 2

Active movement, with gravity eliminated

Grade 3

Active movement against gravity

Grade 4

Active movement against gravity and resistance

Grade 5

Normal power

The MRC scale represents an ordinal scale. Compared with measurements that express strength in Newtons, most muscle power is measured as MRC grade 4–5. Only a minor part of the range of power reflects grades 0–4. There is a large interobserver but small intraobserver variation. Extension of the MRC scale with grades 4–5 can be useful. Other refinements of the scale (MRC 3–4, 4+, 5−) add little diagnostic value.

Recent research using the Rash technique indicated that a more simplified version of the MRC scale with only four modalities (0: paralysis; 1: severe weakness; 2: slight weakness; 3: normal strength) is more reliable to measure strength in patients with immune-mediated neuropathies and Pompe disease.

Table 6. Evaluation of the somatosensory system

Nerve fibers

Qualities

Symptoms

Examination

Exteroceptive system (vital sensation)

Small myelinated or unmyelinated: slow conducting

Pain

Temperature

Crude touch

Neuropathic pain

Analgesia

Hypalgesia Hyperalgesia

Disturbed temperature sense

Sharp point

Two-point discrimination

Proprioceptive system (gnostic sensation)

Large myelinated fibers with thick myelin sheaths: fast conducting

Tactile sense

Vibration sense

Numbness

Tremor

Loss of coordinated movements Postural instability

Wisp of cotton

Rydel–Seiffer tuning fork (128 Hz)

Fingertip–nose test

Romberg test

Tandem walking

Table 7. Diseases with sensory ataxic neuropathy as the accompanying or predominant feature

See also Table 22.1.

sweating, gastrointestinal motility dysfunction, impaired micturition, and male erection dysfunction. Orthostatic hypotension is defined as a decrease in systolic blood pressure of over 20 mmHg and/or a decrease in diastolic pressure of 10 mmHg, three minutes after rising from a supine position. Autonomic dysfunction can be prominent in GBS and other neuropathies (diabetes mellitus and other metabolic diseases, alcohol abuse, paraneoplastic primary amyloidosis), DM type 1, and mitochondrial cytopathy.

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Figure 5. Pes equinovarus in a patient with CMT1A.

Musculoskeletal abnormalities

Disuse of the joints in chronic neuropathy and myopathy may result in contractures and deformity such as clawing of the toes, pes cavus, and pes equinovarus (Figure 5). Weakness of the shoulder muscles causes a frozen shoulder with pain and loss of function of the arm. Winging of the scapula will severely impair abduction of the arm further than 30° as the deltoid muscle cannot function with a loose scapula.

Contractures that are not related to muscle weakness are a feature of Bethlem myopathy (Figure 6). Examples are contractures of the fingers, elbow, Achilles tendon, and torticollis in Bethlem myopathy and of the Achilles tendon, elbow, and posterior cervical muscles (rigid neck) in Emery–Dreifuss muscular dystrophy. Later on in both diseases, limited forward flexion of the thoracic and lumbar spine (rigid spine) may occur.

Abnormalities of posture including scoliosis indicate an onset of a neuromuscular disease before cessation of normal growth. Increased lumbar lordosis may result from weak paraspinal and pelvic muscles; for example, in BMD (Video 7). Increased thoracic kyphosis is the result of weak paraspinal thoracic muscles as seen, for example, in survivors of poliomyelitis. Both postural abnormalities occur in ALS, progressive muscular atrophy (PMA), and Pompe disease. Hyperlaxity can be found in patients with Bethlem and Ullrich myopathies and occasionally in patients with congenital myopathy.

Neuromuscular manifestations are frequently part of a systemic disease (Table 8). Alternatively, in some diseases, other organs and tissues may also be affected; for example, the occurrence of cataracts before the age of 50 years in DM, stroke in mitochondrial cytopathy, gastrointestinal symptoms in DM type 1, and skin abnormalities in dermatomyositis.

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Figure 6. Contractures of the elbows (A) and of the finger flexors (B) in a patient with Bethlem myopathy.
Table 8. Examples of neuromuscular syndromes in systemic diseases

Cardiac function must be evaluated carefully in patients with muscular dystrophy, including BMD, LGMD 2I, Emery–Dreifuss muscular dystrophies, DM types 1 and 2, and mitochondrial cytopathy. Cardiac conduction abnormalities leading to arrhythmia may occur in the progressive and stationary phases of GBS.

Up to 10% of BMD patients have psychomotor retardation. Cognitive decline occurs in DM. In ALS patients, 30%–50% have some frontal dysfunction, and up to 10% of these have overt frontotemporal dementia.

Examination of a patient with a suspected neuromuscular disease

General remarks

A wide range of neuromuscular syndromes is recognized (Table 9). Some characteristic signs suggest one or more neuromuscular diseases (Table 10). The clinical examination starts with observing the patient rising from the chair in the waiting room and walking toward the consultation room. While listening to the history, dysarthria will become evident. The manner and speed of undressing illustrates how signs hamper that activity of daily life. History taking is aimed at unraveling a distinct pattern of complaints (Table 9). The family history may help to provide a rapid diagnosis if a hereditary neuromuscular disease is suspected.

General physical examination

The presence of cardiomyopathy, respiratory insufficiency (Table 11), autonomic failure, arthritis and other skeletal abnormalities, and skin changes or alopecia must be evaluated. The ophthalmologist can establish the presence of a cataract in DM type 1 and type 2, and of retinitis pigmentosa in mitochondrial disease.

Neurological examination

Table 12 gives tips for examining patients with a possible neuromuscular disease. One is advised to examine specifically those parts of the nervous and skeletal muscle systems that are likely to be affected; for example, the legs in a patient with diabetes who could have neuropathy.

Very elaborate examination of the sensory system is usually not necessary if a diagnosis like ALS, myasthenia gravis, or Pompe disease is considered. Patients with Kennedy disease may have sensory neuropathy. Cognition and mental development are assessed if indicated.

Examination of the head and neck, and cranial nerves

Physiological anisocoria of the pupils with a diameter difference of up to 1 mm occurs in 5%–10% of healthy persons. Responses to light and accommodation speed/ability must be reported. Ptosis, ocular movements, and gaze are rapidly assessed. If necessary, provocation tests are done (see also Table 34.1).

The soft palate, tongue, and facial muscles are inspected at rest and during activity. Slight weakness of the orbicularis oculi muscle leaves the eyelashes visible when closing the eye. If the weakness is greater, the sclera can be seen or even Bell’s phenomenon; that is,

Table 9. Common neuromuscular syndromes

Syndrome

Signs

Causes

Remarks

Axonal polyneuropathy:

i.e., more or less symmetric loss of sensation, less prominent motor findings

Distal more than proximal

Legs more affected compared with arms

No walking on heels

Foot drop

If severe: steppage gait

CMT

Diabetes mellitus

Vitamin B1 deficiency

Alcohol

Idiopathic

Vasculitits

Pain may be prominent

Reflexes in the legs can be absent

In most variants of CMT motor > sensory signs

Consider demyelinating neuropathy if arm reflexes are absent

Limb girdle syndrome:

i.e., more or less symmetric weakness of proximal muscles of pelvis and upper legs

Weakness of shoulders and upper arms less prominent

Patient cannot rise from deep chair without help of arms, or climb stairs without holding the railings

Gowers’ sign

(Video 7)

Waddling gait

(Video 7)

Kennedy disease

SMA types 3 and 4

LEMS

BMD

LGMDs

Pompe disease

DM type 2

Myositis

Hypothyroid myopathy

Hip and knee flexor and foot extensor muscles affected early due to physiologically less reserve capacity of muscles

Hip extensor, adductor, and abductor muscles of leg, and foot flexor muscles stronger

If reflexes absent and no skeletal muscle atrophy, consider motor variant of CIDP

Prominent bulbar weakness without diplopia

Dysphagia leading to weight loss and aspiration

Dysarthria

ALS and PMA

Kennedy disease

Myasthenia gravis

Anti-MuSK myasthenia gravis

Mitochondrial cytopathy

OPMD

DM type 1

Patients with Kennedy disease also have limb girdle weakness and postural tremor

Hyperreflexia in ALS

Fluctuating weakness in myasthenia gravis

Prominent bulbar weakness with ptosis and diplopia

Dysphagia causing weight loss and aspiration

Dysarthria

Myasthenia gravis

Anti-MuSK myasthenia gravis

Ptosis and impaired ocular motility in mitochondrial myopathy, OPMD, and DM

Acute respiratory insufficiency

Rapidly progressive weakness and respiratory insufficiency

Deterioration within days to a maximum of 4 wk

GBS

ALS

Myasthenia gravis

Less than 10% of patients with ALS and myasthenia gravis have onset with respiratory insufficiency

Slowly progressive asymmetric atrophy and weakness of hand muscles

Abnormalities suggest motor neuropathy

Progression over months

MMN

Focal SMA

sIBM

No sensory signs

Rarely leg onset

sIBM: deep finger flexors weak

Facial weakness and winged scapula

Facies myopathica

Eye closure incomplete

No diplopia

FSHD

Asymmetry

Winged scapula

Usually increase in winging with forward extension of arms

Increased winging with abduction of arms (weakness of trapezius muscle)

FSHD

LGMD2A

Pompe disease

Spinal accessory nerve lesion

Asymmetry can be prominent

Rhabdomyolysis

Acute (hours–days) muscle pain and limb girdle pattern of weakness, dark urine, very high serum CK levels

Spontaneous recovery in days–weeks

Excessive muscle activity (e.g., seizure)

Crush, trauma

Ischaemia

Drugs (e.g., statins), toxins

Hyperthermia

Viral infection

Myopathy, mainly metabolic and some muscular dystrophies

Myoglobinuria may cause potentially irreversible acute renal failure

Statins are also associated with more gradual-onset necrotizing myopathy, which may persist after discontinuation of the statin and improve with immunosuppressive agents.

We did not aim to present a comprehensive survey of all neuromuscular syndromes as most of these will be discussed in individual Cases. Table 9 can help to rapidly recognize common neuromuscular syndromes.

Table 10. Characteristic signs that suggest one or more diseases

Sign

Disease

Remark

Cataract before age 50 yr

Myotonic dystrophy types 1 and 2

Cardiac involvement (see also Table 38.1)

GBS

DMD and BMD patients and carriers

LGMD1B

LGMD 1E

LGMD 2D-F

LGMD 2I

Emery–Dreifuss MD (patients and carriers)

Myofibrillar myopathies

DM types 1 and 2

Isolated cardiomyopathies are excluded

Skin changes

POEMS syndrome

Lyme radiculoneuritis

Lepromatous neuropathy

Vasculitic neuropathy

Dermatomyositis

Not all features of POEMS syndrome are obligatory with the exception of the M-protein antecedent erythema migrans

Ptosis

MFS (with diplopia and ataxia)

Myasthenia gravis (all forms)

Mitochondrial cytopathy OPMD

DM type 1

Pompe disease

Ptosis can be asymmetric in myasthenia gravis, mitochondrial cytopathy, and Pompe disease

Enlarged tongue

BMD

Amyloid myopathy in primary amyloidosis

Pompe disease

Hypothyroidism

Dropped head

ALS and PMA

CIDP

Myasthenia gravis

Anti-MuSK myasthenia gravis

Central core disease (a congenital myopathy)

DM type 1

Mitochondrial cytopathy

Dermatomyositis and polymyositis

sIBM

Idiopathic isolated neck extensor myopathy (axial myopathy)

Weakness of neck extensor muscles may cause dysphagia

Abnormal flexor contraction in cervical dystonia causes pseudoextensor weakness

Perioral fasciculation

Kennedy disease (Video 10)

Rare in ALS

Percussion-induced rapid muscle contractions, mounding, and rippling

LGMD1C

Deep finger flexor weakness

sIBM

Elbow contracture (see also Table 42.1)

Emery–Dreifuss muscular dystrophy

Desmin myopathy

Bethlem myopathy

Wrist flexors, knee, and ankle contractures also occur

Proximal leg weakness and dry mouth

LEMS

LEMS patients with small-cell lung cancer have rapid progression and early bulbar signs

Asymmetric foot drop

ALS and PMA, focal SMA

Hereditary neuropathy with liability to pressure palsy (HNPP)

MMN

FSHD

sIBM

Compression neuropathy

Vasculitic neuropathy

Can be exercise-induced

Muscle atrophy is not obligatory in early HNPP and MMN

Vasculitic neuropathy is usually associated with acute onset and pain

Sensory ataxia

MFS (with diplopia and ptosis)

Sensory CIDP

Paraneoplastic and nonparaneoplastic, immune-mediated ganglionopathy

Polyneuropathy and IgM monoclonal gammopathy

Mitochondrial disease with POLG1 gene mutation

Postural and kinetic tremor

Kennedy disease

SMA

CMT

Polyneuropathy and IgM monoclonal gammopathy

Table 11. Neuromuscular disorders with early or prominent respiratory failure

upward rotation of the eye. The frontal muscle is inspected when looking upward or frowning. Special attention is paid to facial expression at rest and when laughing, whistling, and pouting the lips. Note that in FSHD, weakness can be very subtle and asymmetric (Figure 7). Weakness of the zygomaticus muscles causes a vertical smile that is often observed in myasthenia gravis and DM (Figure 8).

Table 13. Main action and innervation of the most important muscles
aDeltoid muscle also elevation and retraction of abducted arm; function hampered if supraspinatus muscle is paralyzed.
bExtensor digitorum longus and extensor pollicis longus muscles extend at interphalangeal joints; similar innervation and myelum segments as extensor digitorum and extensor pollicis muscles.
cFlexor digitorum profundus I and II muscles: flection of distal phalanx of index and middle fingers with proximal phalanx fixed (median nerve, C7, C8). Flexor digitorum III and IV muscles have the same function for ring and little finger (ulnar nerve, C7, C8). Deep finger flexor muscles are preferentially involved in IBM.
dHamstrings: biceps femoris, semitendinosus, and semimembranosus muscles.
eTrendelenburg sign: when patient stands on one leg weak gluteus medius and minimus muscle lead to bending over to the other side.
fThe gluteus maximus and hamstring muscles act together when walking, running, and climbing; the gluteus regulates flexion of hip when sitting down).
gDorsiflexion of foot is synonymous with extension.
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Figure 13. DM1. Three-generation family with anticipation. (A) 54-year-old woman with complaints of myotonia from the age of 30 years and progressive weakness since then. Hollow temples and atrophy of the sternocleidomastoid muscles. (B) 32-year-old son with frontal baldness, hollow temples, ptosis and unsmiling, “carp” mouth (also see Figure 9). (C) 28-year-old son without ptosis but with hollow temples, frontal baldness, and unsmiling mouth. Both men had onset during the first decade and psychomotor retardation. The maternal grandfather had cataracts removed at the age of 55 years. He died when 65 years old from cardiac arrest.
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Figure 14. FSHD. Characteristic appearance of the shoulders. The trapezius muscle mounds up when the patient tries to abduct the arms. The shoulder blades slide upward and laterally. With great effort, the patient can keep the arms in the horizontal plane.
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Figure 15. FSHD. Asymmetric winged scapulae. Asymmetry becomes more evident if the patient pushes the outstretched arms against a hard surface.


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