A 62-year-old woman is referred to a tertiary care hospital with a history of diplopia and fatigue for the past 3 months. She has also noticed difficulty in climbing the stairs and combing her hair. She confirms a history of 2.3 kg (5.0 lb) weight loss in the past 6 weeks and constipation. Past medical history is significant for type 2 diabetes mellitus. She has a 50-pack-year cigarette smoking history. Physical examination reveals a blood pressure of 135/78 mm Hg supine and 112/65 while standing, a heart rate of 82/min supine and 81/min while standing, and a temperature of 37.0°C (98.6°F). She is oriented to time and space. Her right upper eyelid is slightly drooped. She has difficulty in abducting the right eye. Pupils are bilaterally equal and reactive to light with accommodation. The corneal reflex is intact. Muscle strength is reduced in the proximal muscles of all 4 limbs, and the lower limbs are affected more when compared to the upper limbs. Deep tendon reflexes are bilaterally absent. After 10 minutes of cycling, the reflexes become positive. Sensory examination is normal. Diffuse wheezes are heard on chest auscultation. Which of the following findings is expected?

Incremental pattern on repetitive nerve conduction studies

Thymoma on CT scan of the chest

Periventricular plaques on MRI of the brain

Antibodies against muscle-specific kinase

A 29-year-old woman presents to the primary care office for a recent history of falls. She has fallen 5 times over the last year. These falls are not associated with any preceding symptoms; she specifically denies dizziness, lightheadedness, or visual changes. However, she has started noticing that both of her legs feel weak. She's also noticed that her carpet feels strange beneath her bare feet. Her mother and grandmother have a history of similar problems. On physical exam, she has notable leg and foot muscular atrophy and 4/5 strength throughout her bilateral lower extremities. Sensation to light touch and pinprick is decreased up to the mid-calf. Ankle jerk reflex is absent bilaterally. Which of the following is the next best diagnostic test for this patient?

Electromyography (including nerve conduction studies)

A 68-year-old man comes to the physician because of double vision and unilateral right eye pain that began this morning. His vision improves when he covers either eye. He has hypertension, mild cognitive impairment, and type 2 diabetes mellitus. The patient has smoked two packs of cigarettes daily for 40 years. His current medications include lisinopril, donepezil, metformin, and insulin with meals. His temperature is 37°C (98.6°F), pulse is 85/minute, respirations are 12/minute, and blood pressure is 132/75 mm Hg. His right eye is abducted and depressed with slight intorsion. He can only minimally adduct the right eye. Visual acuity is 20/20 in both eyes. Extraocular movements of the left eye are normal. An MRI of the head shows no abnormalities. His fingerstick blood glucose concentration is 325 mg/dL. Further evaluation is most likely to show which of the following?

Positive swinging-flashlight test

A 28-year-old man presented with gradually progressive gait disturbances since 10 years of age. His gait was clumsy and slow, and it was very difficult for him to perform brisk walking and running. After a few years, he developed tremors involving both upper limbs along with progressively increasing fatigability. Over the last several months, his friends have noticed that his speech has become slow, slurred, and sometimes incomprehensible. He has also developed difficulty in swallowing recently. On physical examination, he is vitally stable with normal sensorium and normal higher mental functions. The neurological examination reveals absent deep tendon reflexes in the lower extremities and the extensor plantar response bilaterally. Muscle tone is normal in different muscle groups with significant distal muscle wasting in the extremities. There is a marked loss of vibration and position senses. His gait is ataxic and nystagmus is present. His speech is explosive and dysarthric. The neurologist suspected a specific condition and asked for genetic testing, which identified 2 GAA trinucleotide repeat expansions. Which of the following is a correct statement related to the diagnosis of this patient?

The gene locus which is mutated in this condition is on chromosome 9

Gait ataxia in this condition is a pure sensory ataxia

Restrictive cardiomyopathy is seen in approximately 50% of the patients

The condition is inherited as autosomal dominant condition

Vertical nystagmus is characteristically seen in patients with this condition

Autonomic dysfunction syndromes for USMLE Step 1: High-Yield Anatomy Lessons

Intro to Dysautonomia - Body's Broken Autopilot

Dysautonomia: A group of disorders caused by malfunction of the Autonomic Nervous System (ANS)-the body's "autopilot" for vital involuntary functions.
Core Function: The ANS constantly fine-tunes heart rate, blood pressure, digestion, and temperature regulation without conscious input.
Pathophysiology: Results from an imbalance between sympathetic ("fight-or-flight") and parasympathetic ("rest-and-digest") signals.

Autonomic Nervous System: Parasympathetic vs. Sympathetic

Clinical Spectrum: Manifests as a wide range of syndromes with diverse symptoms, from mild orthostatic intolerance to severe systemic failure.

⭐ Dysautonomia is frequently a secondary complication of other systemic diseases (e.g., Diabetes Mellitus, Parkinson's disease, amyloidosis) rather than a primary disorder.

POTS - Heart's Racing Standstill

Definition: Orthostatic intolerance with a marked ↑ in heart rate upon standing, without significant hypotension.
Diagnosis: Occurs within 10 min of standing/tilt-table test.
- Sustained heart rate ↑ of ≥30 bpm (adults) or ≥40 bpm (ages 12-19).
- OR standing heart rate of >120 bpm.
- Absence of orthostatic hypotension (systolic BP drop <20 mmHg).

Tilt Table Test for POTS Diagnosis

Clinical Picture: Predominantly young women. Symptoms include palpitations, lightheadedness, fatigue, "brain fog," and exercise intolerance.

Management:
- Non-Pharm: ↑ fluid & salt intake, compression garments, graded exercise.
- Pharm: Fludrocortisone, midodrine, beta-blockers.

⭐ High-Yield: POTS is frequently associated with Ehlers-Danlos Syndrome (EDS) and Mast Cell Activation Syndrome (MCAS), forming a recognized triad.

Key Syndromes - The System Crashers

Multiple System Atrophy (MSA / Shy-Drager):
- Features: Parkinsonism, ataxia, and early, severe autonomic failure (orthostatic hypotension, incontinence).
- 📌 SHY-Drager: Shaky (Parkinsonism), Hypotensive, Yucky bladder.
Pure Autonomic Failure (PAF / Bradbury-Eggleston):
- Features: Isolated, severe orthostatic hypotension without parkinsonism or ataxia.
- Patho: Lewy bodies confined to peripheral autonomic ganglia.
Familial Dysautonomia (Riley-Day / HSAN III):
- Features: Infancy onset, "alacrima" (no tears), absent fungiform papillae, poor temperature/BP control.
- Genetics: Predominantly in Ashkenazi Jewish populations (IKBKAP gene).
Postural Orthostatic Tachycardia Syndrome (POTS):
- Features: Orthostatic intolerance with HR ↑ by ≥30 bpm (≥40 for ages 12-19) within 10 mins of standing, without significant hypotension.
- Demographics: Commonly affects young women.

⭐ In Multiple System Atrophy (MSA), severe autonomic failure often precedes or develops within 2 years of motor symptom onset, a key feature distinguishing it from Parkinson's disease where autonomic signs appear much later.

Circulatory Alterations in Autonomic Dysfunction Syndromes

Orthostatic hypotension is a cardinal sign (systolic BP ↓ >20 mmHg or diastolic ↓ >10 mmHg).

Multiple System Atrophy (MSA) is marked by autonomic dysfunction plus parkinsonism or cerebellar signs.

Diabetic neuropathy is the most frequent cause, leading to gastroparesis, bladder dysfunction, and orthostatic hypotension.

POTS involves symptomatic tachycardia (HR ↑ >30 bpm) on standing without orthostatic hypotension.

Horner's syndrome is the triad of ptosis, miosis, and anhidrosis from a sympathetic lesion.

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