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.

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Vignette says a 38 year old male presents to the primary care physician with chief complaints of passing dark colored urine in the morning over the past few months; He also reports of fatigue, generalized weakness, occasional headaches, shortness of breath, and intermittent abdominal pain over the past few months; He also reports of multiple episodes of unexplained anemia in the past, requiring occasional blood transfusions; He was previously diagnosed with deep venous thrombosis of the left lower extremity 1 year back and takes warfarin 5 mg once daily; Vital signs show blood pressure of 130/80 mm of Hg, pulse rate of 88 bpm, respiratory rate of 18 breaths/min, oxygen saturation of 98% in RA and temperature of 96.9 F; Examination shows pale bulbar conjunctiva and palms; Laboratory studies show hemoglobin of 8.0 mg/dL, MCV of 100 fL, reticulocyte count of 4% (normal range is 0.5- 2.5%), LDH of 1200 U/L (normal range is 135-225 U/L), indirect bilirubin of 1.8 mg/dL (normal range is 0.2 to 0.8 mg/dL) and low haptoglobin levels; Coombs test is negative; Flow cytometry detects absence of anchored proteins CD55 and CD59; Diagnosis?

Diagnosis is Paroxysmal Nocturnal Hemoglobinuria (PNH).

Paroxysmal Nocturnal Hemoglobinuria (PNH) is caused by the mutation of PIGA gene in hematopoietic stem cells; PIGA gene is required for the synthesis of glycosylphosphatidylinositol (GPI) protein on cell surface; Mutation of PIGA gene leads to deficiency of GPI and subsequently deficiency of its anchored proteins CD55 and CD59 (CD55 and CD59 is secured to the cell membrane by GPI; CD55/DAF and CD59/MIRL are the inhibitors of complement).

Presents with coombs negative hemolytic anemia, pancytopenia and venous thrombosis.

Diagnosis:-

1. CBC shows pancytopenia.

2. Sucrose lysis test is used for screening.

3. Flow cytometry detects absence of anchored proteins CD55 and CD59 and is the confirmatory test. 

4. Laboratory studies show low hemoglobin, increased reticulocytes, increased indirect bilirubin, increased LDH and decreased haptoglobin.

Management:-

1. Supportive measures include iron, folate supplementation, blood transfusions and anticoagulation.

2. Steroids. 

3. Eculizumab is the monoclonal antibodies to C5 that inhibits activation of the terminal complement pathway) and reduces hemolysis; It is associated with increased susceptibility to neisseria infections. Hence, patients should receive meningococcal vaccination before receiving eculizumab.

4. Allogeneic bone marrow transplant.

Sjogren’s syndrome

Vignette says a 38 years old female presents to her primary care physician with chief complaints of dry eyes and dry mouths for the past 6 months; She reports of burning, itching and gritty sensation in both eyes and uses artificial tear drops frequently; She also reports of difficulty swallowing dry foods and needs to drink water frequently while eating foods; Examination shows non tender, enlarged bilateral parotid glands; She was diagnosed with rheumatoid arthritis 2 years back and takes 15 mg of methotrexate once weekly with folinic acid; Vital signs show blood pressure of 120/80 mm of Hg, pulse rate of 78 bpm, respiratory rate of 16 breaths/min, oxygen saturation of 98% in RA and temperature of 96.9 F; Serology shows positive ANA, rheumatoid factor, Anti SS-A (Ro) and Anti SS-B (La) antibodies; Schirmer test shows reduced tear production; Salivary gland biopsy shows lymphocytic infiltration; Diagnosis?

Diagnosis is Sjogren’s syndrome.

Sjogren’s syndrome is an autoimmune disease that leads to destruction of lacrimal and salivary glands due to lymphocytic infiltration; It commonly affects women; It can be divided into primary and secondary (associated with other autoimmune disorders like RA, SLE).

Clinical features:-
1. Dry eyes (keratoconjunctivitis sicca)
2. Dry mouth (xerostomia), dental caries
3. Symmetric painless enlargement of parotid glands
4. Vaginal dryness and dyspareunia
5. Dry skin
6. Extra glandular features include arthritis, vasculitis, interstitial nephritis, interstitial pneumonitis, PNS or CNS disease, PBC, Raynaud phenomenon, cryoglobulinemia.

Diagnosis:-
1. ANA (+) in 90% of cases, RF (+) in 75 % of patients with secondary disease.
2. Anti ribonucleoprotein antibodies (Anti SS-A (Ro) and Anti SS-B (La) antibodies) are positive.
3. Schirmer test to access tear production.
4. Rose Bengal stain shows damaged epithelium of cornea and conjunctiva.
5. Lip (minor salivary gland) biopsy shows lymphocytic infiltration.

Management:-
1. Pilocarpine or Cevimeline (enhance oral and ocular secretions via acetylcholine).
2. Artificial tears for dry eyes.
3. Good oral hygiene.
4. NSAIDs, Steroids, DMARDs for extra glandular manifestations.

Carcinoid syndrome

Vignette says a 55 year old woman presents to the clinic with chief complaints of intermittent facial flushing, diarrhea and wheezing over the past 6 months; She also reports of having occasional episodes of crampy abdominal pain along with nausea, vomiting and loose stools occurring 3-4 times a day; She also complains of unintentional weight loss of 8 kg, in past 6 months; Examination shows holosystolic murmur at the left sternal border on auscultation; Vital signs show blood pressure of 120/80 mm of Hg, pulse rate of 102 bpm, respiratory rate of 18 breaths/min, oxygen saturation of 92% in RA and temperature of 99.9 F; 24-hour urinary excretion of 5-HIAA is increased; MRI of abdomen and pelvis shows small bowel mass with multiple liver metastasis; Diagnosis?

Diagnosis is carcinoid syndrome.

Carcinoid syndrome occurs when a carcinoid tumor (i.e. neuroendocrine tumors) commonly located in the GI tract (e.g. small bowel) metastasizes to the liver as serotonin produced by the tumor cannot be metabolized by the liver and leads to the distinctive clinical features.

Presents with abdominal pain, bronchospasm, flushing and diarrhea. Carcinoid syndrome is associated with right sided valvular lesions (i.e. tricuspid regurgitation, pulmonic stenosis); Triggers include alcohol, stress and spicy food; Triad of dermatitis, dementia, and diarrhea due to niacin deficiency (as tryptophan is shunted towards production of serotonin).

Location of carcinoid tumors:- Bronchus> Ileum > Rectum > Appendix > Colon.

Diagnosis:-

1. 24-hour urinary excretion of 5-HIAA is increased.

2. CT/MRI of abdomen and pelvis to localize the primary or metastatic carcinoid tumors.

3. Octreotide scintigraphy to localize the primary or metastatic carcinoid tumors.

4. Neuroendocrine markers (i.e. chromogranin, synaptophysin) are elevated.

5. Echocardiography shows valvular heart disorders (i.e. tricuspid regurgitation, pulmonic stenosis).

Management:-

1. Avoid triggers, correct electrolytes abnormalities (due to chronic diarrhea), niacin supplementation, loperamide for diarrhea, beta agonists for bronchospasm and antihistamines for flushing. 

2. Somatostatin analogues (e.g. octreotide) for symptom control.

3. Surgical resection for localized tumors.

4. Liver directed therapies (e.g. hepatic artery embolization, radiofrequency ablation, targeted radiotherapy (i.e. smart bombs)) for liver metastases.

HY point:- Chromogranin A and synaptophysin are the most specific immunohistochemical markers for the neuroendocrine tumors (e.g. small cell carcinoma of lung, carcinoid tumor, pheochromocytoma and neuroblastoma).

Acromegaly

Vignette says a 50 year old male presents to the primary care physician with gradual onset of SOB, headache and visual disturbances over the past few months; He also reports of fatigue, snoring at nights and daytime sleepiness; He has a history of hypertension and diabetes for which he takes amlodipine and metformin; On examination, he has coarse facial features with prominent frontal bones and jaw, enlarged feet and hands; Vital signs show blood pressure of 150/90 mm of Hg; Lab shows increased IGF-1; OGT test shows failure of GH suppression; Echocardiography shows left ventricular hypertrophy with EF of 55%; MRI of the brain shows pituitary mass; Diagnosis?

Diagnosis is Acromegaly.

Presents with coarse facial features, macroglossia, enlarged feet and hands, diaphoresis, headache, bitemporal hemianopia, OSA, carpal tunnel syndrome, Type 2 DM, HTN, left ventricular hypertrophy and HFpEF (most common cause of death). 

Diagnosis:- 

1. Increased IGF-1. 

2. OGT test shows failure of suppression of growth hormone with oral glucose suppression test. 

3. MRI shows pituitary mass. 

Management:- 

1. Medical therapy includes:- 

a. Somatostatin analogues (e.g. octreotide). 

b. Dopamine receptor agonist (e.g. Cabergoline, Bromocriptine). 

c. Growth hormone receptor antagonist (e.g. pegvisomant). 

2. Surgical resection of the mass (i.e. transsphenoidal surgery).

De Quervain's thyroiditis

Vignette says a 12 year old female presents the to endocrinology clinic with complaints of painful anterior neck swelling for 15 days; She also reports of palpitations, sweating and difficulty sleeping; She recently had upper respiratory infection (URI) prior to the appearance of neck pain; Vital signs show blood pressure of 110/80 mm of Hg, pulse rate of 102 bpm, respiratory rate of 18 breaths/min, oxygen saturation of 92% in RA and temperature of 99.9 F; Local examination shows diffusely enlarged, tender thyroid glands on palpation; TFT shows low TSH and high T3, & T4 levels; Radioactive iodine uptake (RAIU) is decreased; Diagnosis? 

Diagnosis is De Quervain's thyroiditis (subacute granulomatous thyroiditis). 

De Quervain's thyroiditis is a self-limiting inflammatory condition of the thyroid gland which is commonly triggered by viral infection and is usually associated with HLA-B35.

Clinical features include a history of flu-like illness, i.e. fever and URI (e.g. viral infection), preceded by painful thyroid swelling and neck pain. It presents with the triad of fever, painful thyroid swelling and neck pain.
It leads to transient hyperthyroidism (due to rupture of thyroid follicular cells), followed by an euthyroid state and then hypothyroidism. Patients may be euthyroid, hyperthyroid, or hypothyroid, or may evolve from one to another over time.

Diagnosis:- 
1. TFT usually shows hyperthyroid state as patients present in acute phase, i.e. low TSH and high T3, & T4 levels. 
2. ESR is elevated. 
3. Radioactive iodine uptake (RAIU) is decreased. 
4. Biopsy shows granulomatous inflammation (consisting of giant cells clustered with foci of degenerating thyroid follicles).

Treatment:- Most patients return to normal state within 12-18 months (It is a self-limiting disease). 
1. Analgesics:- Aspirin, NSAIDs are given for mild symptoms, whereas steroids are given for severe symptoms. 
2. Hyperthyroid state is managed with propranolol, whereas hypothyroid state is managed with levothyroxine along with TFT monitoring.

Coarctation of aorta

Vignette says a 35 year old female presents to the cardiology clinic with chief complaints of high blood pressure for the last 5 years for which she takes 3 different types of antihypertensive medications; She also complains of persistent headaches, dizziness, and shortness of breath on exertion over the past years; There is no history of cardiovascular disease in the family; Vital signs show blood pressure of 180/100 mm of Hg in right arm and 130/80 mm of Hg in left arm, pulse rate of 88 beats/min, oxygen saturation is 94% in RA and temperature is 97.4 F; On examination radial pulse is strong and fast whereas femoral pulse is weak and delayed (i.e. radio femoral delay); ECG shows left ventricular hypertrophy; Chest X ray shows bilateral rib notching and focal indentation of the distal aortic arch; Echocardiography shows LVH; Routine laboratory reports are within normal limit; USG (A+P) shows normal scan; Diagnosis?

Diagnosis is coarctation of the aorta. 

Coarctation of aorta is the narrowing of the aorta just distal to the left subclavian likely near the insertion/opening of the ductus arteriosus (i.e. "juxta ductal"); Majority of coarctations are diagnosed during childhood, however some cases remain asymptomatic until adulthood. 

Presents with secondary hypertension, radio femoral delay, disproportionate blood pressure between upper and lower extremities (i.e. BP in upper extremity > lower extremity) and left ventricular hypertrophy. Associated with bicuspid aortic valves.

Diagnosis:- 

1. Chest x ray shows rib notching and '"figure 3 sign". 

2. ECG shows LVH. 

3. Echocardiography shows narrowing of the aorta near the ligamentum arteriosum and LVH. 

4. CT Angiography/Cardiac MRI shows the presence, site and severity of coarctation as well as collateral vessels. 

Management:- 

1. Surgical repair involves excision of the narrowed segment and direct anastomosis of the normal aorta whereas transcatheter repair involves balloon dilation with stent placement.