A 53-year-old woman comes to the physician because of a 3-year history of increasing weakness of her extremities and neck pain that is worse on coughing or sneezing. She first noticed weakness of her right upper extremity 3 years ago, which progressed to her right lower extremity 2 years ago, her left lower extremity 1 year ago, and her left upper extremity 6 months ago. She has had difficulty swallowing and speaking for the past 5 months. Vital signs are within normal limits. Examination shows an ataxic gait. Speech is dysarthritic. Muscular examination shows spasticity and muscle strength is decreased in all extremities. There is bilateral atrophy of the sternocleidomastoid and trapezius muscles. Deep tendon reflexes are 4+ bilaterally. Plantar response shows an extensor response bilaterally. Sensation is decreased below the C5 dermatome bilaterally. Which of the following is the most likely cause of this patient's symptoms?

Cerebral glioblastoma multiforme

A 29-year-old man comes to the emergency department because of progressively worsening fatigue and shortness of breath for the past 2 weeks. His only medication is insulin. Examination shows elevated jugular venous distention and coarse crackles in both lungs. Despite appropriate life-saving measures, he dies. Gross examination of the heart at autopsy shows concentrically thickened myocardium and microscopic examination shows large cardiomyocytes with intracellular iron granules. Examination of the spinal cord shows atrophy of the lateral corticospinal tracts, spinocerebellar tracts, and dorsal columns. Which of the following is the most likely underlying cause of this patient's condition?

GAA trinucleotide repeat expansion on chromosome 9

CTG trinucleotide repeat expansion on chromosome 19

SOD1 gene mutation on chromosome 21

SMN1 gene mutation on chromosome 5

Dystrophin gene mutation on the X chromosome

An 82-year-old comes to the physician for a routine checkup. He feels well. He has a history of hypertension, peripheral vascular disease, carotid stenosis, and mild dementia. His father had Parkinson's disease and died of a stroke at the age of 74 years. He has smoked one-half pack of cigarettes daily for 30 years but quit at the age of 50 years. He drinks alcohol in moderation. Current medications include aspirin and lisinopril. He appears healthy. His temperature is 36.9°C (98.4°F), pulse is 73/min, respirations are 12/min, and blood pressure is 142/92 mmHg. Examination shows decreased pedal pulses bilaterally. Ankle jerk and patellar reflexes are absent bilaterally. Sensation to light touch, pinprick, and proprioception is intact bilaterally. Muscle strength is 5/5 bilaterally. He describes the town he grew up in with detail but only recalls one of three words after 5 minutes. Which of the following is the most appropriate next step in management for these findings?

Prescribe thiamine supplementation

A 13-year-old girl is brought to the physician by her mother because of a 1-month history of abnormal movements of her muscles that she cannot control. She has a younger brother with cognitive disabilities and epilepsy. Examination shows frequent, brief, involuntary contractions of the muscle groups of the upper arms, legs, and face that can be triggered by touch. An EEG shows generalized epileptiform activity. A trichrome stain of a skeletal muscle biopsy specimen shows muscle fibers with peripheral red inclusions that disrupt the normal fiber contour. Which of the following is the most likely underlying mechanism of the patient's symptoms?

Defective oxidative phosphorylation

CTG trinucleotide repeat expansion

Mutation of the methyl-CpG binding protein 2 gene

Autoimmune endomysial destruction

A 55-year-old man is brought to the emergency department by ambulance from a long term nursing facility complaining of severe shortness of breath. He suffers from amyotrophic lateral sclerosis and lives at the nursing home full time. He has had the disease for 2 years and it has been getting harder to breath over the last month. He is placed on a rebreather mask and responds to questions while gasping for air. He denies cough or any other upper respiratory symptoms and denies a history of cardiovascular or respiratory disease. The blood pressure is 132/70 mm Hg, the heart rate is 98/min, the respiratory rate is 40/min, and the temperature is 37.6°C (99.7°F). During the physical exam, he begs to be placed in a sitting position. After he is repositioned his breathing improves a great deal. On physical examination, his respiratory movements are shallow and labored with paradoxical inward movement of his abdomen during inspiration. Auscultation of the chest reveals a lack of breath sounds in the lower lung bilaterally. At present, which of the following muscles is most important for inspiration in the patient?

Muscles of anterior abdominal wall

A 46-year-old man comes to the physician because of a 2-month history of hoarseness and drooling. Initially, he had difficulty swallowing solid food, but now he has difficulty swallowing foods like oatmeal as well. During this period, he also developed weakness in both arms and has had an 8.2 kg (18 lb) weight loss. He appears ill. His vital signs are within normal limits. Examination shows tongue atrophy and pooled oral secretions. There is diffuse muscle atrophy in all extremities. Deep tendon reflexes are 3+ in all extremities. Sensation to pinprick, light touch, and vibration is intact. An esophagogastroduodenoscopy shows no abnormalities. Which of the following is the most likely cause of this patient's symptoms?

Destruction of upper and lower motor neurons

Autoimmune destruction of acetylcholine receptors

Dilation of the central spinal canal

Demyelination of peripheral nerves

In which of the following pathological states would the oxygen content of the trachea resemble the oxygen content in the affected alveoli?

Foreign body obstruction distal to the trachea

Amyotrophic lateral sclerosis for USMLE Step 3: High-Yield Pathology Lessons

ALS Basics - The Motor Meltdown

Amyotrophic Lateral Sclerosis (ALS): Also known as Lou Gehrig's Disease, a relentless, progressive neurodegenerative disorder affecting both upper and lower motor neurons.
Primary Impact: Leads to progressive muscle weakness, atrophy, and eventual paralysis, while sensation and cognition are typically spared early on.

Upper and Lower Motor Neuron Pathways in ALS

⭐ The combination of UMN (spasticity, hyperreflexia) and LMN (fasciculations, atrophy) signs in the same limb is a classic hallmark of ALS.

Pathophysiology - Cellular Sabotage

Genetic & Cellular Insults: A multi-hit process drives neurodegeneration.
- Proteinopathy: Cytoplasmic aggregation of misfolded proteins is a core feature.
  - TDP-43: Mislocalization from nucleus to cytoplasm forms ubiquitinated inclusions.
  - SOD1: Mutations cause toxic protein aggregation and oxidative stress.
- C9orf72 Repeat Expansion: The most common genetic cause, leading to toxic RNA foci and dipeptide repeats.
- Glutamate Excitotoxicity: Excessive synaptic glutamate damages motor neurons.

Protein quality control pathways in ALS

⭐ Bunina bodies, eosinophilic cytoplasmic inclusions in lower motor neurons, are pathognomonic for ALS. They are considered remnants of autophagic vacuoles.

Clinical Picture - Signs of Surrender

Hallmark: A fatal combination of Upper Motor Neuron (UMN) & Lower Motor Neuron (LMN) signs.
- Initial Presentation: Typically asymmetric limb weakness (e.g., foot drop, hand weakness).
- Progression: Relentless and progressive course.
UMN Signs (Spasticity):
- Hyperreflexia, spasticity, and a positive Babinski sign.
LMN Signs (Wasting):
- Fasciculations, atrophy, and flaccid weakness. 📌 Mnemonic: Remember the key contrast: Upper motor neuron signs cause Spasticity, Lower motor neuron signs cause Fasciculations.
Bulbar Involvement:
- Dysarthria: Slurred speech.
- Dysphagia: Swallowing difficulty.
- Pseudobulbar affect: Inappropriate laughing or crying.

⭐ Exam Favorite: Despite widespread motor devastation, sensation, bowel/bladder control, extraocular eye movements, and cognitive functions are classically spared until the very late stages.

Diagnosis & Management - The Battle Plan

Electrophysiology
- Electromyography (EMG): Confirms widespread denervation with fibrillation potentials & fasciculations.
- Nerve Conduction Studies (NCS): Usually normal; helps exclude other neuropathies.
Pharmacologic
- Riluzole: Glutamate inhibitor, may prolong survival.
- Edaravone: Free radical scavenger, may slow functional decline.
Supportive Care
- Ventilation: Non-invasive ventilation (NIV) for respiratory insufficiency.
- Nutrition: Percutaneous endoscopic gastrostomy (PEG) tube for dysphagia.

⭐ Exam Favorite: Despite widespread motor neuron loss, sensory examination, cognition, and extraocular muscle function are classically spared until late in the disease course.

Combined UMN and LMN signs are the hallmark, involving limbs, bulbar, and respiratory muscles.

Presents with asymmetric limb weakness, fasciculations, and hyperreflexia, often starting in one limb.

Sensation, eye movements, and bowel/bladder control are classically spared.

A key genetic link is a mutation in the SOD1 gene (superoxide dismutase 1).

Histopathology shows loss of anterior horn cells and corticospinal tract neurons.

Riluzole may modestly increase survival by decreasing glutamate excitotoxicity.

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