Differential Diagnosis in Neurology

Topic 11. Neuromuscular Junction Disorders

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11.2. Myasthenia Gravis (Acquired and Congenital)

General Features:
- Incidences 4/1,000,000; prevalence 0.5–5/100,000
- Peak incidence 25–30 years of age
- Females greater than males; older age males > females
Clinical Presentation:
- Onset is subacute
- Ptosis of one eyelid most common early sign
- Symptoms and signs vary over time
- Proximal muscle weakness particularly of the lower extremities greater than distal weakness is a common pattern
- Weakness may increase during the day
- Fatigue with exercise of the specific muscle group that is exercised (chewing, swallowing, and holding the head up)
- Clinical involvement is purely ocular in 15% of patients
- Aggravating features for weakness:
  - Exercise
  - Heat
  - Menses
  - Infection (viral)
  - Pregnancy
  - Stress
  - Hypokalemia
  - Thyroid dysfunction
- 40–50% of patients present with ptosis or diplopia; mild ocular deviation often causes blurred vision (non-foveation)
- 20–30% of patients have ocular complaints and muscle weakness
- Bulbar complaints at initial presentation occur in approximately 20% of patients
Clinical examination:
- Ptosis (usually asymmetrical); lifting the ptotic lid causes droop of the other lid
- Normal pupils
- III, IV or Vth nerve weakness
- Pseudo Intranuclear ophthalmoplegia
- Cogan's twitch sign (over activation of co-innervated yoked muscles; over stimulation of levator palpebrae after fatigue of inferior oblique and superior rectus)
- Lower facial muscle weakness (transverse smile); prominent jaw weakness; patients may hold jaw closed with their hand
- Neck flexor and extensor muscle weakness to similar degree (flexors weak with myopathy and extensors weak with motor neuron disease)
- Triple furrowed tongue (differential weakness of intrinsic tongue muscles with unequal tongue muscle contraction)
- Peek-a-boo sign (slight opening of the eyelids occurs after forced eyelid closure (weakness of the orbicularis oculi)
- Sluggish gag reflex, difficulty swallowing liquids and nasal speech
- Weakness proximal greater than distal; lower extremities are involved to greater degree than upper
- Weakness worsened by repetitive use
- Reflexes normal to increased (spread of acetylcholine sensitivity of the sarcolemmal membrane)
- Respiratory weakness may appear as an isolated sign
- Isolated distal limb weakness and neck extensor weakness
- Difficulty weaning a patient from a respirator
- Rarely isolated bulbar weakness

Course of the Illness

90–95% of patients develop extraocular muscle weakness
20% may have only ocular involvement
40% develop bulbar weakness
60–75% extremity weakness
Patients who present with pure extraocular motor manifestation that generalize do so within two years
Mortality now at less than 3%
After three years, approximately 60% of patient with ocular myasthenia gravis generalize

Associated Medical Illnesses

Thyroid disorder (10%; most commonly hyperthyroidism)
Rheumatoid arthritis
Platelet abnormalities (ITP) idiopathic thrombocytopenic purpura
Antibodies to gastric parietal cells with B12 deficiency
Diabetes mellitus
Hemolytic anemia
Sjögren's syndrome
Lymphoma
Nonspecific immunologic abnormalities:
- Serum anti-muscle Ab
- Antibodies against thyroid, gastric parietal cell and nuclear antigens

Thymic Abnormalities

Thymic pathology in 75–80% of patients
Ten to 15% have thymoma; most frequently seen in 55–65 year old males
Young women demonstrate thymic hyperplasia

EMG Evaluation

Jolly response is positive in 85% of patient with generalized MG
At least a 10% decrement between the first and fourth compound muscle action potential (CMAP) at 2–3 HZ
30–40% will have negative repetitive stimulation in pure ocular MG
In the face of a decremental response:
- Maximal contraction of the muscle for 30 to 60 seconds abolishes the decrement (post-tetanic potentiation) for 120 seconds after exercise
- The decrement is increased (post-tetanic exhaustion) for 120–240 seconds following exercise
Single fiber electromyography:
- Jitter (latency variability between single muscle fiber potentials) innervated by the same axon is increased in MG
- Blocking (absence of the second muscle fiber potential) may be noted
- Single fiber EMG is abnormal in 95–100% of MG patients
Laboratory evaluation:
- Antibodies to acetylcholine receptor:
  - Positive in 85–90% of patients with generalized MG
  - Positive in 30–40% of patients with ocular MG
- Pulmonary function tests
  - Abnormal spirometry
  - Decreased mean ventilatory volume
    - Fatigue
    - Restrictive pattern
- CT scan of the chest
  - Evaluation for thymic tumors
- Blood evaluation to rule out associated autoimmune disease

Serum Antibodies to Muscle Specific Receptor Tyrosine Kinase (MuSK)

Clinical Features:
- Found in generalized seronegative MG patients; 20% of MG patients
- All patients were women
- Onset between 12–59 years of age
- Neck, shoulder or respiratory weakness
- Less prominent ocular muscle involvement
- Variable response to cholinesterase inhibitors
- EMG may be myopathic

Myasthenia Gravis with Thymoma

Predominantly a disease of middle aged males
- Clinical Presentation:
  - Ptosis is frequent; less often other cranial nerves are involved
  - May lose reflexes
  - May have sensory complaints: paraesthesia; deep muscle ache
  - Difficulty initiating movements
  - Anti-striated A-band muscle antibodies
  - Patients with serum antibodies to the alpha 1 or alpha 3 containing neuronal AChR subunits had autonomic symptoms
- Paraneoplastic disease associated with thymoma (lymphoepithelial thymoma in one patient) developed in sequential order:
  - Limbic encephalitis
  - Neuromyotonia (with hyperhidrosis and motor neuropathy)
  - Myasthenia gravis
- Associated diseases with thymoma:
  - Hypogammaglobinemia (Good's syndrome)
  - Macrocytic anemia, thrombocytosis and hypogammaglobinemia
  - Thymoma-associated autoimmune enteropathy
  - Loss of CD19 + lymphocytes in peripheral blood
  - Pure red cell aplasia
  - Polymyositis (rare)
  - Intersitial myocarditis

Differential Diagnosis of Myasthenia Gravis (Ocular Involvement Alone)

Brainstem lesions affecting the IIIrd nerve (pupil often involved); pseudo internuclear ophthalmoplegia from MG (convergence often affected)
Horner's Syndrome (pupil is miotic)
Painless ptosis over several days (MG)
Alternating and recurrent ptosis (MG)
Graves ophthalmopathy:
- All ocular muscles enlarge
- Pathological retraction of the globe
- Forced ductions demonstrate decreased motility
Kearns-Sayre Syndrome
- Associated heart block
Progressive external ophthalmoplegia
- Symmetric ptosis
- Associated myocardiopathy nerve and proximal muscle weakness
- Slow saccades; MG rapid saccades within limits of weakness
Aneurysm (P-COM)
- Retroorbital pain
- Pupillary involvement; often oval
Diabetes III nerve involvement:
- Sudden onset of dysfunction
- No pupillary involvement
Autoimmune thyroid disease
- May coexist with MG
- Periorbital pain

Differential Diagnosis of Generalized MG Central Disorders

Brainstem lesions (associated long tract signs)
Basilar meningitis (fever, stiff neck)
Demyelinating disease (sensory loss: cerebellar signs; optic nerve dysfunction)

Neuromuscular disease

ALS (bulbar presentation)
Diphtheria (pupils involved)
Polymyositis (swallowing)
Inclusion body myositis (swallowing)
Granulomatous myopathy

Neuromuscular Junction Disease

Lambert–Eaton Syndrome:
- Autonomic involvement (dry mouth)
- "Load in the pants" gait
- Minimal ptosis (less cranial nerve involvement)
- Exercise induced increased strength
Congenital myasthenic syndromes
- Initiation at birth
- Gradual deterioration of motor function

Congenital Myasthenia Syndrome Resembling Lambert–Eaton (LES) Pre-Synaptic Syndrome

EMG characteristics of LES
Defect of the presynaptic voltage gated calcium channels (VGCC) in the synaptic release complex
EMG:
- CMAP is low at rest
- 100% facilitation at high stimulation frequencies

Paucity of Synaptic Vesicles and Reduced Quantal Release

Symptoms resemble those of acquired MG
Defect of synthesis or axonal transport of vesicle precursors to axon terminals
Less than 20% of the usual Ach quanta released by a nerve impulse
Partial response to acetylcholinesterase inhibitors

Post Synaptic Congenital Myasthenia Syndrome (CMS)

General features:
- All are caused by mutations in AchR subunit genes
  - Increase or decrease the synaptic response to Ach
  - The genes coding for alpha and delta subunits of the AchR are on chromosome 2q; beta and epsilon subunits as on different loci on chromosome 17p

End Plate Choline Acetyl Transferase Deficiency

General Features:
- No AchR defect
- MEPP amplitudes normal at rest
  - Decreases during 10-Hz stimulation for 10 minutes
  - Defect in resynthesis or packaging of vesicular Ach quanta
Clinical Presentation:
- Sudden episodes of apnea
- Precipitants are fever excitement or infection
- Presents at birth with bulbar dysfunction respiratory weakness (ventilatory support) and hypotonia
- Recurrent apneic attacks with bulbar paralysis; may occur in later life
- Some patients are not breathing at birth and experience attacks during infancy or early childhood
- Ptosis and fatigable weakness may persist between attacks
- Extraocular muscles may be spared
- Sluggish pupillary light reflex
- Refractory to cholinesterase inhibitors
EMG:
- Repetitive CMAP
Pathology:
- Absence of AchR at the synaptic cleft
- Small nerve terminals encased by Schwann cells; decreased quantal release

Increased Response to Acetylcholine

Slow-Channel Syndromes:
- Varied clinical presentation:
  - Early severe syndrome
  - Late presentation with little disability
- Cervical wrist and finger extensor muscle involvement
- Prolonged openings of the AchR
- AD inheritance
- Quinine may be effective
EMG:
- Repetitive CMAP and end plate potentials demonstrate staircase summation with depolarization block

Decreased Response to Acetylcholine

General features:
- Clinical symptoms resemble acquired MG
- Mild to severe weakness
- Due to low affinity of ligand
- Due to gating abnormality
- Due to mode switching kinetics

Decreased Response to Acetylcholine

Fast Channel Syndromes

General Features (3 syndromes):
- All syndromes have brief channel openings
- Decreased probability of channel opening
- Responsive to:
  - Pyridostigmine
  - 3.4 diamino pyridine
- Low-Affinity fast channel syndromes:
  - Normal AchR and end plate morphology
  - Infrequent and briefer than normal channel openings
  - Mutation of the extracellular domain of the epsilon subunit (ε P121L)
- Fast channel syndrome due to a gating abnormality
  - Mutation of the M3 domain of the alpha subunit (α V285I)
  - Small MEPP and decreased miniature end plate conductance
    - Slow channel-opening rate constant beta
    - Fast channel-closing rate constant alpha
    - Reduced probability of channel opening
- Fast channel syndrome due to mode switching kinetics
  - In frame duplication in the long cytoplasmic loop of E, E1254 in 18
    - Reduces AchR expression
  - Gate opens more slowly
  - Closes more rapidly than normal

Primary Acetylcholine Receptor Deficiency with or without Minor Kinetic Abnormalities

Homozygous and heterozygous recessive mutation in AchR subunit genes
Mild to severe symptoms similar to acquired autoimmune MG
Partial response to acetylcholinesterase inhibition and 3,4-diaminopyridine
Severe end plate AchR deficiency:
- Mutations of the ε subunit of the AchR

Congenital Myasthenic Syndromes Associated with Pectin Deficiency

Pectin is an intermediate filament linking protein; concentrated at sites of mechanical stress
In association with recessive form of epidermolysis bullosa simplex and muscular dystrophy
Pectin is decreased in skin and absent from muscle in these conditions

Differential Diagnosis of Congenital Myasthenic Syndrome in Adults

Mitochondrial myopathy
Motor neuron disease
FSH dystrophy
LGMD
Sero positive and sero negative autoimmune MG