# Clinical Cases: Autonomic Nervous System ## Case 1: Horner Syndrome - Sympathetic Pathway Disruption ### Clinical Image ![Horner Syndrome](case_01_image.jpg) *Source: [Wikimedia Commons - Horner's Syndrome and Autonomic innervation](https://commons.wikimedia.org/wiki/File:Horner%27s_Syndrome_and_Autonomic_innervation_of_the_eye.svg) - CC BY-SA 4.0* ### Patient Presentation A 58-year-old male smoker presents to the emergency department with a 2-week history of right-sided drooping eyelid and decreased sweating on the right side of his face. He also reports persistent right shoulder pain radiating down his arm for the past month. He has lost 15 pounds unintentionally over 3 months and notes a new chronic cough. He denies headache, trauma, or recent neck manipulation. ### Demographics - Age: 58 years - Sex: Male - Risk factors: 40 pack-year smoking history - Duration: 2 weeks of eye symptoms, 1 month of shoulder/arm pain ### Chief Complaint Right-sided ptosis, decreased facial sweating, and shoulder/arm pain ### Physical Examination - Vital signs: BP 138/86, HR 78, RR 16, Temp 37.0C - HEENT: - Right eye: Ptosis (2mm), miosis (constricted pupil), anisocoria more pronounced in dim light - Right face: Anhidrosis (decreased sweating) on right forehead and face - No enophthalmos apparent - Pupillary light reflex intact bilaterally - Neurological: Decreased sensation in C8-T1 distribution on right, 4/5 grip strength right hand - Respiratory: Decreased breath sounds in right apex - Lymph nodes: Right supraclavicular lymphadenopathy ### Workup - Cocaine eye drops (4%): Right pupil fails to dilate (confirms Horner syndrome - cocaine blocks norepinephrine reuptake; requires intact sympathetic pathway) - Hydroxyamphetamine drops (1%): Right pupil fails to dilate (indicates postganglionic lesion - this drug releases stored norepinephrine from intact postganglionic neurons) - Chest X-ray: Right apical mass - CT chest with contrast: 4 cm mass in right lung apex invading chest wall, consistent with Pancoast tumor - MRI brachial plexus: Tumor invasion of lower brachial plexus (C8-T1) and stellate ganglion - CT-guided biopsy: Non-small cell lung carcinoma (squamous cell) ### Diagnosis Pancoast Tumor (superior sulcus tumor) causing Horner Syndrome and brachial plexus involvement ### Treatment 1. Oncology consultation for staging workup (PET scan, brain MRI) 2. Multidisciplinary tumor board discussion 3. If resectable: Neoadjuvant chemoradiation followed by surgical resection 4. Pain management: Neuropathic pain regimen (gabapentin, opioids as needed) 5. Smoking cessation 6. Palliative care involvement for symptom management 7. Eye care: Artificial tears (if decreased tear production) ### Physiological Principles Demonstrated - **Sympathetic pathway anatomy**: The three-neuron sympathetic pathway to the eye: (1) First-order neuron: hypothalamus to ciliospinal center at C8-T2; (2) Second-order neuron: exits spinal cord, passes over lung apex, synapses in superior cervical ganglion; (3) Third-order neuron: travels with internal carotid to orbit. - **Horner syndrome triad**: - **Ptosis**: Loss of sympathetic input to Mueller's muscle (superior tarsal muscle) causes mild ptosis (2-3mm, less than CN III palsy) - **Miosis**: Loss of sympathetic input to the dilator pupillae muscle causes relative miosis; unopposed parasympathetic tone constricts the pupil - **Anhidrosis**: Loss of sympathetic input to facial sweat glands; distribution depends on lesion location (face and neck for pre-ganglionic; forehead only for post-ganglionic) - **Pharmacological localization**: Cocaine test confirms Horner (blocks NE reuptake, requiring intact pathway); hydroxyamphetamine test localizes to postganglionic if pupil fails to dilate (releases stored NE from intact postganglionic neurons) - **Dual innervation of the pupil**: Pupil size reflects balance between parasympathetic (constrictor, via CN III) and sympathetic (dilator) tone. Loss of one reveals unopposed action of the other. - **Pancoast syndrome**: Apical lung tumors can involve the lower brachial plexus (C8-T1 causing hand weakness and Klumpke-type sensory loss), stellate ganglion (causing Horner syndrome), and parietal pleura (causing shoulder/arm pain). --- ## Case 2: Pheochromocytoma - Catecholamine Excess ### Clinical Image ![Pheochromocytoma](case_02_image.jpg) *Source: [Wikimedia Commons - Pheochromocytoma Scan](https://commons.wikimedia.org/wiki/File:Pheochromocytoma_Scan.jpg) - CC BY-SA 3.0* ### Patient Presentation A 42-year-old female presents to her primary care physician with episodes of severe headache, palpitations, and profuse sweating occurring several times per week for the past 6 months. Episodes last 15-30 minutes and are often triggered by physical exertion or emotional stress. Between episodes, she feels relatively well but notes persistent anxiety. During one episode in the office, her blood pressure was measured at 220/130 mmHg, which normalized to 145/92 between episodes. She has no significant past medical history but mentions her father had thyroid cancer. ### Demographics - Age: 42 years - Sex: Female - Family history: Father with thyroid cancer (raises suspicion for MEN2) ### Chief Complaint Episodic severe headaches, palpitations, diaphoresis, and paroxysmal hypertension ### Physical Examination During Episode: - Vital signs: BP 218/128, HR 128, RR 22, diaphoretic, tremulous - General: Anxious, pale, diaphoretic - Cardiovascular: Tachycardic, regular rhythm Between Episodes: - Vital signs: BP 148/94, HR 82 - Thyroid: No palpable nodules - Skin: Cafe-au-lait spots noted (concerning for neurofibromatosis, associated with pheochromocytoma) ### Workup - 24-hour urine catecholamines and metanephrines: Markedly elevated (norepinephrine 1,250 mcg/24h [normal <80], normetanephrine 4,500 mcg/24h [normal <900]) - Plasma free metanephrines: Elevated - CT abdomen: 4.5 cm right adrenal mass with heterogeneous enhancement, Hounsfield units >10 - MIBG (I-123 metaiodobenzylguanidine) scan: Uptake in right adrenal mass, no extra-adrenal disease - Genetic testing: RET proto-oncogene mutation identified (MEN2A) - Screening: Calcitonin elevated (medullary thyroid cancer); calcium/PTH normal - Echocardiogram: Mild LVH, normal EF (catecholamine-induced cardiomyopathy screening) ### Diagnosis Pheochromocytoma as part of Multiple Endocrine Neoplasia Type 2A (MEN2A) ### Treatment 1. **Preoperative alpha-blockade first**: Phenoxybenzamine 10 mg BID, titrate to control BP (target BP <130/80 seated, >90 standing) 2. **Then beta-blockade** (after adequate alpha-blockade): Metoprolol or propranolol for tachycardia 3. High-salt diet and fluids to expand contracted intravascular volume 4. Surgical resection: Laparoscopic adrenalectomy after 10-14 days of medical preparation 5. Intraoperative management: Arterial line, prepared for hypertensive crisis and hypotension post-tumor removal 6. MEN2A management: Prophylactic thyroidectomy for medullary thyroid cancer (high RET mutation risk) 7. Genetic counseling and screening of first-degree relatives 8. Lifelong surveillance for recurrence and contralateral pheochromocytoma ### Physiological Principles Demonstrated - **Adrenal medulla as modified ganglion**: Chromaffin cells are developmentally related to sympathetic postganglionic neurons but release catecholamines directly into the bloodstream (epinephrine 80%, norepinephrine 20%). - **Catecholamine synthesis**: Tyrosine → DOPA → Dopamine → Norepinephrine → Epinephrine. Pheochromocytomas may secrete predominantly norepinephrine (as in this case) or epinephrine. - **Adrenergic receptor effects**: - **Alpha-1**: Vasoconstriction → hypertension, pallor - **Beta-1**: Increased HR and contractility → palpitations, tachycardia - **Beta-2**: Sweating (sympathetic cholinergic to most sweat glands, but adrenergic effects occur with circulating epinephrine) - **Why alpha-blockade first**: Beta-blockers alone would block beta-2 vasodilation (skeletal muscle), leaving alpha-1 vasoconstriction unopposed → paradoxical worsening of hypertension. Alpha-blockade must precede beta-blockade. - **Volume contraction**: Chronic catecholamine excess causes vasoconstriction and pressure natriuresis, contracting plasma volume. After tumor removal, loss of vasoconstriction → profound hypotension unless volume is repleted preoperatively. - **Episodic symptoms**: Tumor releases catecholamines intermittently, often triggered by tumor manipulation, exercise, anesthesia, or certain foods/medications. --- ## Case 3: Orthostatic Hypotension - Autonomic Failure ### Clinical Image ![Orthostatic Hypotension](case_02_image.jpg) *Source: Clinical illustration of baroreceptor reflex and autonomic dysfunction* ### Patient Presentation A 72-year-old male with a 15-year history of type 2 diabetes mellitus presents with recurrent near-syncope and falls over the past year. Episodes occur when he stands up from sitting or lying down, particularly in the morning or after meals. He reports feeling lightheaded and having "graying" of vision when standing. He also mentions longstanding erectile dysfunction, constipation alternating with diarrhea, urinary hesitancy with incomplete bladder emptying, and inability to sense when his bladder is full. His diabetes has been poorly controlled for years. ### Demographics - Age: 72 years - Sex: Male - Past Medical History: Type 2 DM x 15 years, HbA1c 9.2%, peripheral neuropathy ### Chief Complaint Recurrent near-syncope and falls when standing ### Physical Examination Supine: - BP: 152/88 mmHg, HR: 76 bpm Standing (after 3 minutes): - BP: 98/62 mmHg (drop >20 systolic, >10 diastolic), HR: 78 bpm (minimal increase - impaired reflex) Additional findings: - Neurological: Stocking-glove sensory loss to light touch and vibration, absent ankle reflexes - Cardiovascular: No carotid bruits, regular rhythm - Extremities: Dry skin, decreased hair on lower legs, diminished pedal pulses ### Workup - Orthostatic vital signs: Confirmed >20 mmHg systolic drop without appropriate heart rate increase - ECG: Normal sinus rhythm, no conduction abnormalities - Echocardiogram: Normal LV function (rules out cardiac cause) - Tilt-table testing: Neurogenic orthostatic hypotension confirmed (BP drops without compensatory tachycardia) - Autonomic function tests: - Heart rate variability with deep breathing: Reduced (parasympathetic dysfunction) - Valsalva maneuver: Absent overshoot and reduced heart rate response - Quantitative sudomotor axon reflex test (QSART): Reduced sweat output in feet - Post-void residual: 180 mL (indicates neurogenic bladder) - HbA1c: 9.2% ### Diagnosis Diabetic Autonomic Neuropathy with Neurogenic Orthostatic Hypotension ### Treatment 1. Non-pharmacological measures first: - Rise slowly from sitting/lying - Leg crossing and squatting when symptomatic - Compression stockings (waist-high, 30-40 mmHg) - Increase salt intake (if no contraindication) and fluid intake - Elevate head of bed 10-15 degrees at night - Avoid large meals, alcohol, and hot environments 2. Medication review: Discontinue or reduce diuretics, alpha-blockers, and other offending medications 3. If refractory, pharmacotherapy: - Midodrine (alpha-1 agonist) 5-10 mg TID (not at bedtime - causes supine hypertension) - Fludrocortisone 0.1-0.2 mg daily (volume expansion via mineralocorticoid effect) - Droxidopa (norepinephrine prodrug) for neurogenic orthostatic hypotension 4. Aggressive glycemic control to prevent further neuropathy progression 5. Manage other autonomic symptoms: - Gastroparesis: Small frequent meals, metoclopramide - Neurogenic bladder: Timed voiding, consider intermittent catheterization - Erectile dysfunction: PDE5 inhibitors ### Physiological Principles Demonstrated - **Baroreceptor reflex**: Upon standing, blood pools in lower extremities due to gravity, reducing venous return and cardiac output. Baroreceptors in the carotid sinus and aortic arch detect the pressure drop and signal the medulla to increase sympathetic and decrease parasympathetic output, raising heart rate and vasoconstriction to maintain BP. - **Neurogenic vs. non-neurogenic OH**: In neurogenic OH (as in diabetic autonomic neuropathy), heart rate fails to increase appropriately because sympathetic efferent pathways are damaged. In non-neurogenic causes (e.g., volume depletion), heart rate increases appropriately. - **Autonomic tone concept**: At rest, both sympathetic and parasympathetic systems maintain tonic activity. Loss of sympathetic vascular tone (vasoconstriction) contributes to orthostatic hypotension. Loss of parasympathetic variability reduces heart rate responsiveness. - **Diabetic autonomic neuropathy spectrum**: Involves multiple systems - cardiovascular (orthostatic hypotension, resting tachycardia, reduced heart rate variability), gastrointestinal (gastroparesis, constipation, diarrhea), genitourinary (bladder dysfunction, erectile dysfunction), and sudomotor (anhidrosis in feet, compensatory hyperhidrosis elsewhere). - **Midodrine mechanism**: Direct alpha-1 adrenergic agonist causes vasoconstriction, raising peripheral resistance and blood pressure. Must be avoided at bedtime to prevent supine hypertension. - **Fludrocortisone mechanism**: Synthetic mineralocorticoid promotes renal sodium and water retention, expanding plasma volume to compensate for reduced vasoconstrictor response.