Myasthenia gravis

Vignette says a 35 year old woman presents to her primary care physician with chief complaints of progressive muscle weakness over the past few months; She initially noticed difficulty keeping her eyelids open particularly in the evening; She also reports of difficulty swallowing (dysphagia), slurred speech (dysarthria) and double vision (diplopia) particularly in the evening which eventually improves with rest; She also reports weakness in her legs and arms, especially after walking or using her arms for prolonged periods; Examination shows normal deep tendon reflexes with no sensory deficits; Fatigability test is positive; Vital signs are normal; Laboratory studies show positive anti-acetyl choline receptor antibodies and anti-MUSK (muscle specific kinase) antibodies; Edrophonium test shows improvement of motor function for a few minutes; Electromyography shows progressive decline in muscle action potential amplitude with repetitive stimulation; MRI of the chest shows thymoma; Diagnosis?

Diagnosis is Myasthenia gravis. 

Myasthenia gravis is an autoimmune disorder of muscle weakness that occurs due to production of auto antibodies against acetylcholine receptors present at the postsynaptic neuromuscular junction; Associated with HLA-DR3; It is commonly present in young woman; Usually associated with thymoma (paraneoplastic syndrome) as 30% of the patients with thymoma develop Anti-acetylcholine receptor antibodies and subsequently myasthenia gravis.

Clinical Features:-

1. The cardinal feature of the MG is the fluctuating weakness with the fatigability (i.e. worsens with repetitive use and relief by rest); Vignette says a young woman with ptosis, diplopia, dysphagia, and dysarthria that worsens particularly in the evening; Exacerbations triggered by stressors such as infections, surgery, pregnancy, and medications (e.g. aminoglycosides and fluoroquinolones).

Diagnosis:-

1. Anti-Acetyl choline receptor antibodies are positive.

2. Anti-MUSK (muscle specific kinase) antibodies are positive.

3. Tensilon test:- Edrophonium is a short acting acetylcholinesterase inhibitor; temporarily increases acetylcholine in NMJ and leads to improvement of motor function for a few minutes.

4. Electromyography shows progressive decline in muscle action potential amplitude with repetitive stimulation.

5. Ice Pack test shows improvement of neuromuscular transmission after application of ice packs in affected muscles for 10 minutes.

Treatment:-

1. Long acting acetylcholinesterase inhibitors (e.g. neostigmine, pyridostigmine).

2. Steroids (e.g. prednisolone).

3. Immunosuppressive drugs (e.g. azathioprine, tacrolimus, cyclophosphamide, or mycophenolate are used in order to get the patient off of steroids). 

4. IVIG and/or plasmapheresis (generally used in myasthenic crisis for rapid response).

5. Thymectomy if thymoma is present.

6. Avoid fluoroquinolones and aminoglycosides (exacerbate myasthenia).

Cushing disease

Vignette says a 45 year old female presents to her primary care physician with chief complaints of irregular menstruation, weight gain, and fatigue over the past 8 months; Examination shows abdominal striae, facial hair and central obesity with thin extremities; Vital signs show blood pressure of 150/90 mm of Hg; Laboratory studies show random blood sugar of 258 mg/dL, elevated 24 hour urinary free cortisol levels, elevated serum ACTH levels and failure of suppression of cortisol with low dose dexamethasone whereas suppression of cortisol is evident with large dose dexamethasone; MRI shows pituitary mass; Diagnosis?

Diagnosis is Cushing’s disease; Cushing’s disease is characterized by increased ACTH production from the anterior pituitary gland.

Cushing’s syndorme

Etiologies:-

1. Iatrogenic:- MCC; Low ACTH and High Cortisol; Bilateral adrenal gland atrophy.

2. Adrenal Cushing’s:- 2nd MCC; Low ACTH and High Cortisol; Unilateral adrenal gland atrophy.

3. Pituitary Cushing’s:- MC endogenous cause; High ACTH and High Cortisol; Bilateral adrenal glands hyperplasia.

4. Ectopic Cushing’s:- Paraneoplastic ACTH secretion; High ACTH and High Cortisol; Bilateral adrenal glands hyperplasia.

Diagnosis:-

1. Screening tests to diagnose cushing's syndrome include elevated 24 hour urinary free cortisol levels, elevated level of salivary cortisol and inadequate suppression of cortisol on low dose dexamethasone test.

2. Differentiating tests for cause of cushing's syndrome (to r/o cushing's disease, ectopic ACTH secretion and adrenal tumors):-

a. Measure serum ACTH levels:- Decreased in adrenal tumors whereas Increased in ectopic ACTH secretion and cushing's disease (because they secrete ACTH independent of the HPA axis).

b. High dose dexamethasone test:- No suppression in ectopic ACTH secretion whereas adequate suppression in cushing's disease.

c. CRH stimulation test:- Increase in ACTH and cortisol in cushing's disease whereas no Increase in ACTH and cortisol in ectopic ACTH secretion.

Clinical Features:-

1. Redistribution of fat:- Central (truncal) obesity, moon facies, buffalo hump, supraclavicular fat pads with wasting of extremities or thin extremities (i.e. proximal myopathy; Increased CK levels).

2. Hypertension, hyperglycemia, hypokalemia.

3. Weight gain, osteoporosis, skin hyperpigmentation (due to increase in ACTH) with easy skin bruising and striae.

4. Acne, hirsutism, amenorrhea (these following symptoms are due to androgen excess).

5. Depression, insomnia, psychosis (these are mental symptoms of Cushing's syndrome).

Management:-

1. Cushing's disease (pituitary adenoma):- Transsphenoidal surgery (endoscopic transsphenoidal surgery is the mainstay of treatment); Radiation therapy if unresectable, surgery fails.

2. Ectopic ACTH-secreting:- Surgical removal of ectopic ACTH secreting tumors (e.g. resection of small cell carcinoma of lung).

3. Adrenal tumors:- Adrenalectomy is done in case of adrenal tumors. (e.g. ketoconazole, metyrapone may be used in inoperable patients (as it decreases cortisol production)).

4. Iatrogenic steroid therapy:- Gradual steroid taper (to prevent addisonian Crisis).

Lifelong glucocorticoid replacement therapy after transsphenoidal surgery whereas lifelong glucocorticoid and mineralocorticoid replacement therapy after surgical or medical bilateral adrenalectomy. 

Osteopetrosis

Vignette says a 7 year old male child presents to the pediatric clinic with complaints of frequent bone fractures, recurrent infections and visual impairment; His mother reports that he has had multiple fractures, even with minimal trauma over the past few years; His mother also reports that he has had several episodes of pneumonia and ear infections requiring hospitalizations in the past; Examination shows pale conjunctiva, macrocephaly with frontal bossing and hepatosplenomegaly; Neurological examination shows decreased visual acuity in both eyes and decreased hearing in both ears; Complete blood count (CBC) shows pancytopenia; X-ray shows diffuse osteosclerosis; Bone marrow biopsy shows dense, sclerotic bone with little marrow space; Diagnosis?

Diagnosis is Osteopetrosis. 

Osteopetrosis (also known as "marble bone disease"), is a genetic disorder characterized by defective osteoclast function leading to impaired bone resorption and the accumulation of abnormally dense bones.

Pathophysiology:- Deficiency of carbonic anhydrase → failure to resorb bone by osteoclasts (i.e. poor osteoclast function due to type II carbonic anhydrase deficiency). 

Clinical features:- 

1. Thick bones which fracture easily (i.e. pathologic fractures).

2. Vision and hearing impairment.

3. CN deficits and hydrocephalus (due to narrowing of foramen in the brain).

4. Type II RTA (i.e. proximal RTA).

5. Pancytopenia and hepatosplenomegaly (due to bone expansion leading to bone marrow narrowing and extramedullary hematopoiesis).

Diagnosis:- 

1. CBC shows pancytopenia.

2. X-ray shows diffuse osteosclerosis (aka “marble bone disease”). 

3. Elevated tartrate-resistant acid phosphatase (TRAP). 

4. Genetic testing shows mutation in the CLCN7 or TCIRG1 gene.

5. Bone marrow biopsy shows dense, sclerotic bone with little marrow space.

Management:- 

1. Supportive measures include pain management, physical therapy, and management of recurrent infections.

2. Calcium and vitamin D supplementation.

3. Erythropoietin or blood transfusions for anemia.

4. IFN-gamma (as it activates osteoclasts).

5. Bone marrow transplantation is the only curative treatment.