Myasthenia gravis

A 35 year old woman presents to her primary care physician with progressive muscle weakness over the past few months. She initially noticed difficulty keeping her eyelids open, especially in the evening. She also reports diplopia, dysphagia, and dysarthria, which worsen with activity and improve with rest. She also reports weakness in her arms and legs, particularly after prolonged use. On examination, deep tendon reflexes are normal, pupils are normal, and there are no sensory deficits. Fatigability is present. Vital signs are normal. Laboratory studies show positive anti-acetylcholine receptor antibodies. Repetitive nerve stimulation shows a decremental response. MRI of the chest reveals a thymoma. Diagnosis?

Diagnosis is Myasthenia gravis.

1. Definition

Myasthenia gravis is an autoimmune disorder of the neuromuscular junction characterized by fluctuating muscle weakness due to antibodies against postsynaptic proteins, most commonly the acetylcholine receptor.

2. Pathophysiology

1. Autoantibodies against acetylcholine receptors (AChR), MuSK, or LRP4
2. In AChR MG, antibodies activate complement, causing destruction of the postsynaptic membrane
3. In MuSK MG, antibodies disrupt the Agrin–LRP4–MuSK complex without complement activation
4. Leads to reduced acetylcholine receptor density
5. Results in reduced safety factor of neuromuscular transmission
6. Weakness worsens with repeated use

3. Clinical Features

3.1 Core Features

1. Fluctuating weakness that worsens with activity and improves with rest
2. Symptoms are worse later in the day

3.2 Ocular Involvement

1. Ptosis
2. Diplopia
3. Present in approximately 85 percent of cases initially

3.3 Bulbar Involvement

1. Dysphagia
2. Dysarthria
3. Hoarseness

3.4 Limb Weakness

1. Proximal muscles more affected than distal
2. Upper limbs more affected than lower limbs

3.5 Examination Findings

1. Normal reflexes
2. No sensory deficits
3. Pupils are spared
4. Weakness demonstrated with repetitive use

4. Associated Conditions

1. Thymic hyperplasia
2. Thymoma present in approximately 10 percent of patients
3. Association with other autoimmune diseases

5. Diagnosis

1. Anti-acetylcholine receptor antibodies present in most generalized cases
2. Anti-MuSK antibodies in a subset
3. Electrophysiologic testing
• Repetitive nerve stimulation shows decremental response
• Single fiber electromyography is the most sensitive test
4. Edrophonium test
• May show transient improvement
• Rarely used now
5. Ice pack test improves ptosis
6. Chest imaging (CT or MRI) to evaluate for thymoma

6. Triggers and Exacerbating Factors

1. Infections
2. Surgery
3. Stress
4. Pregnancy
5. Drugs such as:
• Aminoglycosides
• Fluoroquinolones
• Beta blockers
• Neuromuscular blocking agents

7. Management

7.1 Symptomatic Treatment

1. Pyridostigmine is first line

7.2 Immunosuppressive Therapy

1. Corticosteroids
2. Azathioprine as first line steroid sparing agent
3. Other agents include mycophenolate, cyclosporine, tacrolimus, and methotrexate

7.3 Rapid Therapy

1. Intravenous immunoglobulin (IVIG)
2. Plasmapheresis
• Used in myasthenic crisis

7.4 Surgical

1. Thymectomy
• Indicated in thymoma
• Recommended in many AChR positive patients aged 15 to 50 years
• Not typically recommended in MuSK MG without thymoma

8. Complications

1. Myasthenic crisis causing respiratory failure
2. Aspiration pneumonia
3. Adverse effects of long term immunosuppression

9. Key Clinical Insight

Fluctuating weakness + ocular symptoms + fatigability + normal reflexes + spared pupils + positive AChR antibodies = Myasthenia gravis

10. Exam Level Pearls

1. Weakness worsens with use and improves with rest
2. Ocular symptoms are most common initial presentation
3. Reflexes and sensation are normal
4. Pupils are spared
5. Single fiber EMG is most sensitive
6. Pyridostigmine is first line therapy
7. Thymoma occurs in about 10 percent of patients
8. Myasthenic crisis is life threatening
9. Lambert Eaton improves with use, MG worsens with use

Cushing Syndrome

A 45 year old female presents to her primary care physician with complaints of irregular menstruation, weight gain, and fatigue over the past 8 months. On examination, she has central obesity, abdominal striae, hirsutism, and thin extremities. Blood pressure is 150/90 mmHg. Laboratory studies reveal hyperglycemia, elevated 24 hour urinary free cortisol, elevated ACTH, and failure of suppression with low dose dexamethasone. High dose dexamethasone test shows suppression of cortisol. MRI reveals a pituitary mass. Diagnosis?

Diagnosis is Cushing disease.

1. Definition

Cushing disease is a form of ACTH dependent Cushing syndrome caused by a pituitary adenoma secreting excess ACTH, leading to hypercortisolism.

2. Etiology of Cushing Syndrome

1. Exogenous glucocorticoid use is the most common cause overall
• Low ACTH, high cortisol, bilateral adrenal atrophy
2. Pituitary adenoma (Cushing disease) is the most common endogenous cause
• High ACTH, high cortisol, bilateral adrenal hyperplasia
3. Ectopic ACTH secretion
• High ACTH, high cortisol, typically no suppression with high dose dexamethasone
4. Adrenal tumors
• Low ACTH, high cortisol, unilateral adrenal mass

3. Pathophysiology

1. Excess ACTH causes bilateral adrenal hyperplasia
2. Leads to excessive cortisol production
3. Loss of normal diurnal variation of cortisol
4. Cortisol effects include:
• Protein catabolism leading to muscle wasting
• Gluconeogenesis causing hyperglycemia
• Mineralocorticoid effects causing hypertension
5. Hypokalemia may occur, but is more prominent in ectopic ACTH syndrome

4. Clinical Features

4.1 Fat Redistribution

1. Central obesity
2. Moon facies
3. Buffalo hump
4. Supraclavicular fat pads
5. Thin extremities due to muscle wasting

4.2 Skin Changes

1. Purple striae
2. Easy bruising
3. Skin thinning

4.3 Metabolic Features

1. Hypertension
2. Hyperglycemia

4.4 Endocrine Features

1. Hirsutism
2. Acne
3. Amenorrhea or oligomenorrhea

4.5 Neuropsychiatric Features

1. Depression
2. Insomnia
3. Cognitive changes

5. Diagnosis

5.1 Screening for Hypercortisolism

1. Elevated 24 hour urinary free cortisol
2. Elevated late night salivary cortisol
3. Low dose dexamethasone suppression test showing no suppression
4. At least two abnormal tests are required

5.2 Determining ACTH Dependence

1. Elevated ACTH indicates ACTH dependent disease

5.3 Differentiation of Cause

1. High dose dexamethasone suppression test
• Suppression present in Cushing disease
• No suppression in ectopic ACTH secretion
2. CRH stimulation test
• Increased ACTH and cortisol in pituitary disease
3. Inferior petrosal sinus sampling
• Gold standard
• Central to peripheral ACTH ratio greater than 3 confirms pituitary source

5.4 Imaging

1. Pituitary MRI
2. Most lesions are microadenomas less than 10 mm

6. Management

6.1 First Line

1. Transsphenoidal surgical resection

6.2 Persistent or Recurrent Disease

1. Repeat surgery or radiotherapy

6.3 Medical Therapy

1. Pituitary directed therapy
• Pasireotide
• Cabergoline
2. Adrenal steroidogenesis inhibitors
• Ketoconazole
• Metyrapone
• Osilodrostat
3. Glucocorticoid receptor antagonist
• Mifepristone

7. Complications

1. Hypertension
2. Diabetes mellitus
3. Osteoporosis
4. Infections
5. Muscle wasting
6. Psychiatric disorders

8. Prognosis and Follow Up

1. Untreated disease increases mortality
2. Recurrence can occur
3. Requires lifelong follow up

9. Key Clinical Insight

Central obesity + striae + hypertension + hyperglycemia + elevated ACTH + suppression with high dose dexamethasone + pituitary mass = Cushing disease

10. Exam Level Pearls

1. Cushing disease is the most common endogenous cause
2. High dose dexamethasone suppression distinguishes pituitary from ectopic ACTH
3. Inferior petrosal sinus sampling is the gold standard
4. Transsphenoidal surgery is first line treatment
5. Always confirm hypercortisolism before localization

Torsades de pointes

A 55 year old female with a history of depression presents to the emergency department after an episode of syncope. She reports lightheadedness and palpitations prior to transient loss of consciousness, followed by spontaneous recovery. She was recently treated for a urinary tract infection with ciprofloxacin and is taking citalopram. On examination, findings are unremarkable. Vital signs show blood pressure 100/60 mmHg, pulse 55/min, respiratory rate 18/min, oxygen saturation 98% on room air, and temperature 97.9°F. ECG shows prolonged QT interval (QTc > 500 ms) and polymorphic ventricular tachycardia with twisting of QRS complexes around the isoelectric line. Diagnosis?

Diagnosis is Torsades de pointes.

1. Definition

Torsades de pointes is a polymorphic ventricular tachycardia that occurs in the setting of a prolonged QT interval, characterized by cyclic twisting of QRS complexes around the baseline.

2. Pathophysiology

1. Prolonged QT interval due to delayed ventricular repolarization
2. Caused by inhibition of delayed rectifier potassium currents (IKr)
3. Leads to early afterdepolarizations
4. Often triggered by R on T phenomenon
5. May be pause dependent, occurring after a long RR interval

3. Etiology

3.1 Acquired Causes

1. QT prolonging drugs
• Antiarrhythmics such as class IA and class III
• Antibiotics such as macrolides and fluoroquinolones
• Antidepressants such as SSRIs (citalopram) and TCAs
• Antipsychotics
• Antiemetics such as ondansetron
2. Electrolyte abnormalities
• Hypokalemia
• Hypomagnesemia
• Hypocalcemia
3. Bradycardia

3.2 Congenital Causes

1. Congenital long QT syndrome
• Romano Ward syndrome
• Jervell and Lange Nielsen syndrome

4. Clinical Features

1. Palpitations
2. Dizziness
3. Syncope
4. May progress to ventricular fibrillation and sudden cardiac death

5. ECG Findings

1. QTc > 500 ms significantly increases risk
2. Polymorphic ventricular tachycardia
3. Twisting QRS complexes around isoelectric line

6. Management

6.1 Immediate Measures

1. Discontinue offending drugs
2. Correct electrolyte abnormalities, especially potassium and magnesium

6.2 Hemodynamically Unstable

1. Immediate unsynchronized defibrillation

6.3 Hemodynamically Stable

1. Intravenous magnesium sulfate (2 g IV) is first line therapy
2. Effective even if serum magnesium is normal

6.4 Refractory Cases

1. Increase heart rate to shorten QT interval
2. Isoproterenol for acquired torsades
3. Overdrive pacing

7. Special Considerations

1. Avoid QT prolonging drugs
2. Maintain potassium in high normal range
3. Avoid isoproterenol in congenital long QT syndrome
4. Consider implantable cardioverter defibrillator (ICD) in recurrent or high risk cases

8. Key Clinical Insight

Syncope + QTc > 500 ms + polymorphic VT with twisting QRS + QT prolonging drugs = Torsades de pointes

9. Exam Level Pearls

1. Magnesium sulfate is first line regardless of serum level
2. QT prolonging drugs are the most common cause
3. Bradycardia increases risk
4. Pause dependent arrhythmia is characteristic
5. Combination of citalopram and ciprofloxacin increases risk