A 15-year-old boy is brought to the emergency department one hour after sustaining an injury during football practice. He collided head-on into another player while wearing a mouthguard and helmet. Immediately after the collision he was confused but able to use appropriate words. He opened his eyes spontaneously and followed commands. There was no loss of consciousness. He also had a headache with dizziness and nausea. He is no longer confused upon arrival. He feels well. Vital signs are within normal limits. He is fully alert and oriented. His speech is organized and he is able to perform tasks demonstrating full attention, memory, and balance. Neurological examination shows no abnormalities. There is mild tenderness to palpation over the crown of his head but no signs of skin break or fracture. Which of the following is the most appropriate next step?
Q2
A 4-month-old infant is brought to the emergency department with seizures. CT scan reveals bilateral subdural hematomas of different ages and retinal hemorrhages. Which of the following mechanisms best explains these findings?
Q3
A 38-year-old man comes to the physician for a follow-up examination. He has quadriparesis as a result of a burst fracture of the cervical spine that occurred after a fall from his roof 1 month ago. He has urinary and bowel incontinence. He appears malnourished. His temperature is 37.1°C (98.8°F), pulse is 88/min, and blood pressure is 104/60 mm Hg. Examination shows spasticity in all extremities. Muscle strength is decreased in proximal and distal muscle groups bilaterally. Deep tendon reflexes are 4+ bilaterally. Plantar reflex shows extensor response bilaterally. Sensation to pinprick and temperature is absent below the neck. Sensation to vibration, position, and light touch is normal bilaterally. Rectal tone is decreased. There is a 1-cm area of erythema over the sacrum. Which of the following is the most likely cause of this patient's symptoms?
Q4
A 2-month-old boy is brought to the emergency room by his mother who reports he has appeared lethargic for the past 3 hours. She reports that she left the patient with a new nanny this morning, and he was behaving normally. When she got home in the afternoon, the patient seemed lethargic and would not breastfeed as usual. At birth, the child had an Apgar score of 8/9 and weighed 2.8 kg (6.1 lb). Growth has been in the 90th percentile, and the patient has been meeting all developmental milestones. There is no significant past medical history, and vaccinations are up-to-date. On physical examination, the patient does not seem arousable. Ophthalmologic examination shows retinal hemorrhages. Which of the following findings would most likely be expected on a noncontrast CT scan of the head?
Q5
A 66-year-old woman is brought to the emergency department 4 hours after falling and hitting her head while skiing. Initially, she refused treatment, but an hour ago she began to develop a severe headache, nausea, and right leg weakness. She has osteopenia. Her only medication is a daily multivitamin. She has no visual changes and is oriented to person, time, and place. Her temperature is 37.2°C (99°F), pulse is 72/min, respirations are 18/min and regular, and blood pressure is 128/75 mm Hg. Examination shows a 5-cm bruise on the left side of her skull. The pupils are equal, round, and reactive to light and accommodation. Muscle strength is 0/5 in her right knee and foot. Which of the following is the most likely cause of this patient's symptoms?
Q6
A 57-year-old man was brought into the emergency department unconscious 2 days ago. His friends who were with him at that time say he collapsed on the street. Upon arrival to the ED, he had a generalized tonic seizure. At that time, he was intubated and is being treated with diazepam and phenytoin. A noncontrast head CT revealed hemorrhages within the pons and cerebellum with a mass effect and tonsillar herniation. Today, his blood pressure is 110/65 mm Hg, heart rate is 65/min, respiratory rate is 12/min (intubated, ventilator settings: tidal volume (TV) 600 ml, positive end-expiratory pressure (PEEP) 5 cm H2O, and FiO2 40%), and temperature is 37.0°C (98.6°F). On physical examination, the patient is in a comatose state. Pupils are 4 mm bilaterally and unresponsive to light. Cornea reflexes are absent. Gag reflex and cough reflex are also absent. Which of the following is the next best step in the management of this patient?
Q7
A 35-year-old woman presents with headaches and seizures. MRI shows a well-circumscribed, calcified frontal lobe mass. Histology reveals oligodendroglioma with 1p/19q codeletion and IDH1 mutation. She undergoes gross total resection. Two years later, surveillance MRI shows a new enhancing nodule at the resection margin. Biopsy shows increased mitotic activity, microvascular proliferation, and retained 1p/19q codeletion but new CDKN2A/B homozygous deletion. What is the most critical factor in determining management strategy?
Q8
A 55-year-old man presents with progressive supranuclear gaze palsy, axial rigidity, and frequent falls. MRI shows midbrain atrophy with hummingbird sign. He dies 7 years later. Autopsy reveals globose neurofibrillary tangles in the basal ganglia and brainstem. Tau immunostaining shows 4-repeat tau predominance. His brother had similar symptoms. Genetic testing reveals a MAPT mutation. How does this change the pathogenic understanding and potential therapeutic approach?
Q9
A 70-year-old man with progressive dementia undergoes autopsy. Microscopy shows neuritic plaques and neurofibrillary tangles meeting criteria for Alzheimer disease (AD). However, sections also reveal Lewy bodies in the substantia nigra and cortex, moderate atherosclerosis with old lacunar infarcts, and TDP-43 positive inclusions in the hippocampus. He had no parkinsonian features clinically. What is the most appropriate neuropathologic interpretation?
Q10
A 42-year-old woman presents with behavioral changes, memory loss, and myoclonus. MRI shows cortical ribboning and T2 hyperintensity in the caudate and putamen. EEG shows periodic sharp wave complexes. CSF 14-3-3 is elevated, but real-time quaking-induced conversion (RT-QuIC) is negative. PRNP gene sequencing reveals E200K mutation. Her mother died of similar symptoms at age 45. What feature distinguishes this case from sporadic disease?
CNS trauma US Medical PG Practice Questions and MCQs
Question 1: A 15-year-old boy is brought to the emergency department one hour after sustaining an injury during football practice. He collided head-on into another player while wearing a mouthguard and helmet. Immediately after the collision he was confused but able to use appropriate words. He opened his eyes spontaneously and followed commands. There was no loss of consciousness. He also had a headache with dizziness and nausea. He is no longer confused upon arrival. He feels well. Vital signs are within normal limits. He is fully alert and oriented. His speech is organized and he is able to perform tasks demonstrating full attention, memory, and balance. Neurological examination shows no abnormalities. There is mild tenderness to palpation over the crown of his head but no signs of skin break or fracture. Which of the following is the most appropriate next step?
A. Discharge without activity restrictions
B. Discharge and refrain from all physical activity for one week
C. Observe for 6 hours in the ED and refrain from contact sports for one week (Correct Answer)
D. Administer prophylactic levetiracetam and observe for 24 hours
E. Administer prophylactic phenytoin and observe for 24 hours
Explanation: ***Observe for 6 hours in the ED and refrain from contact sports for one week***
- This patient experienced a brief period of **confusion, headache, dizziness**, and **nausea** immediately after a head injury, which are symptoms consistent with a **mild traumatic brain injury (mTBI)** or **concussion**.
- Although his symptoms have resolved at presentation, observation in the ED for a few hours is prudent to ensure no delayed onset of more severe symptoms, and he should **refrain from contact sports** for at least one week as part of concussion management.
*Discharge without activity restrictions*
- Discharging without activity restrictions is unsafe given the initial symptoms of **confusion** and the potential for delayed symptom presentation or complications from a concussion.
- Concussion management requires a period of **physical and cognitive rest** to allow the brain to heal and prevent **second impact syndrome**.
*Discharge and refrain from all physical activity for one week*
- While refraining from all physical activity for one week is part of concussion management, discharging immediately without any observation period after initial neurological symptoms could be risky.
- An observation period allows for monitoring of any **worsening neurological signs** or symptoms that might indicate a more serious injury.
*Administer prophylactic levetiracetam and observe for 24 hours*
- **Prophylactic anticonvulsants** like levetiracetam are typically not recommended for routine management of **mild traumatic brain injury** or concussion.
- Their use is generally reserved for patients with more severe injuries, evolving conditions, or those who have had **seizures post-trauma**.
*Administer prophylactic phenytoin and observe for 24 hours*
- Similar to levetiracetam, **phenytoin** is an anticonvulsant and its prophylactic use is not indicated for **mild head injuries** or concussions.
- Anticonvulsant prophylaxis is associated with potential side effects and is reserved for specific high-risk scenarios, such as **severe TBI** or **penetrating head trauma**.
Question 2: A 4-month-old infant is brought to the emergency department with seizures. CT scan reveals bilateral subdural hematomas of different ages and retinal hemorrhages. Which of the following mechanisms best explains these findings?
A. Infectious meningitis
B. Acceleration-deceleration forces (Correct Answer)
C. Birth trauma
D. Genetic coagulopathy
E. Direct impact trauma
Explanation: ***Acceleration-deceleration forces***
- **Bilateral subdural hematomas of different ages** and **retinal hemorrhages** are classic findings in **abusive head trauma (shaken baby syndrome)**, caused by severe acceleration-deceleration forces.
- These forces lead to the tearing of **bridging veins** and vitreoretinal traction, resulting in these distinct injuries.
*Infectious meningitis*
- While it can cause seizures, meningitis typically presents with **fever**, **lethargy**, and neck stiffness, and would not cause **subdural hematomas** or **retinal hemorrhages**.
- Its effects on the brain are usually due to inflammation and increased intracranial pressure, not traumatic injury.
*Birth trauma*
- **Birth trauma** might cause subdural hematomas, but they would typically be **acute** and of a **single age**, directly related to the birthing process.
- It is highly unlikely to cause hematomas of "different ages" in a 4-month-old infant, nor would it characteristically cause retinal hemorrhages without other signs of severe, acute trauma.
*Genetic coagulopathy*
- A **genetic coagulopathy** could predispose to bleeding, but it would typically result in more widespread or spontaneous internal bleeding, not specifically **bilateral subdural hematomas** accompanied by **retinal hemorrhages** without other trauma.
- The "different ages" of the hematomas also strongly suggest recurrent episodes of trauma rather than an underlying bleeding disorder.
Question 3: A 38-year-old man comes to the physician for a follow-up examination. He has quadriparesis as a result of a burst fracture of the cervical spine that occurred after a fall from his roof 1 month ago. He has urinary and bowel incontinence. He appears malnourished. His temperature is 37.1°C (98.8°F), pulse is 88/min, and blood pressure is 104/60 mm Hg. Examination shows spasticity in all extremities. Muscle strength is decreased in proximal and distal muscle groups bilaterally. Deep tendon reflexes are 4+ bilaterally. Plantar reflex shows extensor response bilaterally. Sensation to pinprick and temperature is absent below the neck. Sensation to vibration, position, and light touch is normal bilaterally. Rectal tone is decreased. There is a 1-cm area of erythema over the sacrum. Which of the following is the most likely cause of this patient's symptoms?
A. Hemi-transection of the spinal cord
B. Cavitation within the spinal cord
C. Injury to gray matter of the spinal cord
D. Occlusion of the posterior spinal artery
E. Damage to the anterior spinal artery (Correct Answer)
Explanation: ***Damage to the anterior spinal artery***
- This typically results in **anterior cord syndrome**, characterized by bilateral loss of pain and temperature sensation, motor function (quadriparesis), and autonomic dysfunction (bowel/bladder incontinence below the level of injury).
- The **preservation of posterior column functions** (vibration, proprioception, light touch) is a hallmark of anterior spinal artery ischemia, as the posterior columns are supplied by the posterior spinal arteries.
*Hemi-transection of the spinal cord*
- This describes **Brown-Séquard syndrome**, which involves ipsilateral loss of motor function, vibration, and proprioception, and contralateral loss of pain and temperature sensation.
- The patient's symptoms are inconsistent with Brown-Séquard syndrome due to the **bilateral presentation of motor and sensory deficits**.
*Cavitation within the spinal cord*
- This condition, known as **syringomyelia**, typically presents with a **cape-like distribution of pain and temperature loss** (due to central cord involvement affecting the decussating spinothalamic fibers).
- It would usually spare motor function initially and would not explain the sudden, severe quadriparesis and complete sensory loss described.
*Injury to gray matter of the spinal cord*
- Isolated gray matter injury, often seen in conditions like **central cord syndrome**, primarily affects the pain and temperature pathways and may cause upper extremity weakness.
- It would not explain the **complete loss of motor function and pain/temperature sensation below the neck** while preserving posterior column function.
*Occlusion of the posterior spinal artery*
- Occlusion of the posterior spinal artery would primarily affect the **dorsal columns**, leading to loss of vibration, proprioception, and light touch.
- This patient, however, has **preserved sensation to vibration, position, and light touch**, making posterior spinal artery occlusion unlikely.
Question 4: A 2-month-old boy is brought to the emergency room by his mother who reports he has appeared lethargic for the past 3 hours. She reports that she left the patient with a new nanny this morning, and he was behaving normally. When she got home in the afternoon, the patient seemed lethargic and would not breastfeed as usual. At birth, the child had an Apgar score of 8/9 and weighed 2.8 kg (6.1 lb). Growth has been in the 90th percentile, and the patient has been meeting all developmental milestones. There is no significant past medical history, and vaccinations are up-to-date. On physical examination, the patient does not seem arousable. Ophthalmologic examination shows retinal hemorrhages. Which of the following findings would most likely be expected on a noncontrast CT scan of the head?
A. Lens-shaped hematoma
B. Cortical atrophy
C. Crescent-shaped hematoma (Correct Answer)
D. Blood in the basal cisterns
E. Multiple cortical and subcortical infarcts
Explanation: ***Crescent-shaped hematoma***
- The clinical presentation with **lethargy**, a history of being with a **new caregiver**, and **retinal hemorrhages** strongly suggests **abusive head trauma** (shaken baby syndrome).
- This typically results in a **subdural hematoma**, which appears as a **crescent-shaped collection of blood** on a noncontrast CT scan, reflecting bleeding into the potential space between the dura mater and arachnoid mater.
*Lens-shaped hematoma*
- A **lens-shaped (biconvex) hematoma** on CT is characteristic of an **epidural hematoma**, which typically results from a **skull fracture** tearing a meningeal artery.
- While head trauma is present, the specific findings (retinal hemorrhages, lack of skull fracture mention, and mechanism of shaking) are more consistent with subdural rather than epidural bleeding.
*Cortical atrophy*
- **Cortical atrophy** refers to the shrinking of brain tissue and is typically seen in chronic conditions like **neurodegenerative diseases** or **long-standing severe malnutrition**.
- It does not explain the acute onset of lethargy and retinal hemorrhages immediately following a potential traumatic event in an otherwise healthy infant.
*Blood in the basal cisterns*
- **Blood in the basal cisterns** is characteristic of **subarachnoid hemorrhage**, which can be caused by ruptured aneurysms (rare in infants), arteriovenous malformations, or severe trauma.
- While abusive head trauma can sometimes cause subarachnoid bleeding, the primary finding in shaken baby syndrome is usually subdural hemorrhage, and retinal hemorrhages specifically point towards the shearing forces causing subdural bleeding.
*Multiple cortical and subcortical infarcts*
- **Multiple cortical and subcortical infarcts** indicate areas of brain tissue death due to **interrupted blood supply**, as seen in severe stroke or vasculitis.
- This is not the primary or most likely finding in abusive head trauma, though severe head trauma can sometimes lead to secondary ischemic injury due to increased intracranial pressure or vascular disruption.
Question 5: A 66-year-old woman is brought to the emergency department 4 hours after falling and hitting her head while skiing. Initially, she refused treatment, but an hour ago she began to develop a severe headache, nausea, and right leg weakness. She has osteopenia. Her only medication is a daily multivitamin. She has no visual changes and is oriented to person, time, and place. Her temperature is 37.2°C (99°F), pulse is 72/min, respirations are 18/min and regular, and blood pressure is 128/75 mm Hg. Examination shows a 5-cm bruise on the left side of her skull. The pupils are equal, round, and reactive to light and accommodation. Muscle strength is 0/5 in her right knee and foot. Which of the following is the most likely cause of this patient's symptoms?
A. Upward brainstem herniation
B. Extracranial herniation
C. Uncal herniation
D. Subfalcine herniation (Correct Answer)
E. Tonsillar herniation
Explanation: ***Subfalcine herniation***
- The patient's presentation with a **traumatic brain injury** followed by **delayed neurological symptoms** including severe headache, nausea, and contralateral leg weakness suggests a mass effect on the brain.
- **Subfalcine herniation** occurs when the **cingulate gyrus** is pushed under the **falx cerebri**, often compressing the **anterior cerebral artery** and causing **contralateral leg weakness** as seen in this patient.
*Upward brainstem herniation*
- This type of herniation typically involves the cerebellum moving upward through the **tentorial incisura**, often presenting with **oculomotor nerve dysfunction** and **loss of consciousness**.
- The patient's mental status is preserved, and she does not exhibit typical signs of brainstem compression.
*Extracranial herniation*
- **Extracranial herniation** refers to brain tissue protruding outside the cranial vault, usually through a **skull defect** or after **craniectomy**.
- This patient has no mention of a skull defect or prior surgery that would predispose her to this type of herniation.
*Uncal herniation*
- **Uncal herniation** involves the medial temporal lobe (uncus) moving over the **tentorium cerebelli**, classically causing ipsilateral **fixed and dilated pupil** due to **oculomotor nerve (CN III) compression**.
- The patient's pupils are equal, round, and reactive to light, which rules out major uncal herniation.
*Tonsillar herniation*
- **Tonsillar herniation** involves the **cerebellar tonsils** descending through the **foramen magnum**, compressing the brainstem and often leading to **respiratory and cardiac irregularities**.
- The patient's vital signs are stable, and she does not have respiratory or cardiac symptoms indicative of tonsillar herniation.
Question 6: A 57-year-old man was brought into the emergency department unconscious 2 days ago. His friends who were with him at that time say he collapsed on the street. Upon arrival to the ED, he had a generalized tonic seizure. At that time, he was intubated and is being treated with diazepam and phenytoin. A noncontrast head CT revealed hemorrhages within the pons and cerebellum with a mass effect and tonsillar herniation. Today, his blood pressure is 110/65 mm Hg, heart rate is 65/min, respiratory rate is 12/min (intubated, ventilator settings: tidal volume (TV) 600 ml, positive end-expiratory pressure (PEEP) 5 cm H2O, and FiO2 40%), and temperature is 37.0°C (98.6°F). On physical examination, the patient is in a comatose state. Pupils are 4 mm bilaterally and unresponsive to light. Cornea reflexes are absent. Gag reflex and cough reflex are also absent. Which of the following is the next best step in the management of this patient?
A. Second opinion from a neurologist
B. Withdraw ventilation support and mark time of death
C. Electroencephalogram
D. Repeat examination in several hours
E. Apnea test (Correct Answer)
Explanation: ***Apnea test***
- The patient exhibits classic signs of **brain death**, including a **coma**, fixed and dilated pupils, and absent brainstem reflexes (corneal, gag, cough). The next step is to perform an apnea test to confirm the absence of spontaneous respiratory drive.
- An apnea test confirms brain death by demonstrating the **absence of respiratory effort** despite a rising pCO2, provided that spinal cord reflexes are not mistaken for respiratory efforts.
*Second opinion from a neurologist*
- While consulting a neurologist is often helpful in complex neurological cases, the current clinical picture presents such clear signs of brain death that **further confirmatory testing** for brain death (like the apnea test) is more immediately indicated before seeking additional opinions on diagnosis.
- A second opinion would typically be sought to confirm the diagnosis or guide management, but establishing brain death requires a specific protocol which is incomplete without the apnea test.
*Withdraw ventilation support and mark time of death*
- It is **premature to withdraw ventilation** before brain death is unequivocally confirmed by all necessary clinical and confirmatory tests, including the apnea test.
- Withdrawing support without full confirmation could lead to ethical and legal issues, as the patient might still have residual brainstem function, however minimal.
*Electroencephalogram*
- An **EEG** can show absent electrical activity, supporting brain death, but it is **not a mandatory part of the core brain death criteria** in many protocols, especially when clinical signs are clear and an apnea test can be performed.
- The primary diagnostic criteria for brain death usually prioritize clinical examination and the apnea test for proving irreversible cessation of all brain functions.
*Repeat examination in several hours*
- Repeating the examination in several hours is typically done if there are **confounding factors** (e.g., severe hypothermia, drug intoxication) that might mimic brain death, or if the initial assessment is incomplete.
- In this case, there are no mentioned confounding factors, and the immediate priority is to complete the brain death protocol with an apnea test, given the current clear clinical picture.
Question 7: A 35-year-old woman presents with headaches and seizures. MRI shows a well-circumscribed, calcified frontal lobe mass. Histology reveals oligodendroglioma with 1p/19q codeletion and IDH1 mutation. She undergoes gross total resection. Two years later, surveillance MRI shows a new enhancing nodule at the resection margin. Biopsy shows increased mitotic activity, microvascular proliferation, and retained 1p/19q codeletion but new CDKN2A/B homozygous deletion. What is the most critical factor in determining management strategy?
A. The tumor has progressed to anaplastic oligodendroglioma requiring combined chemoradiation with temozolomide and RT
B. CDKN2A/B deletion indicates transformation to glioblastoma requiring maximal therapy
C. Retained 1p/19q codeletion predicts continued chemosensitivity to PCV regimen (Correct Answer)
D. Loss of IDH1 mutation suggests new primary tumor requiring re-resection only
E. Microvascular proliferation mandates anti-angiogenic therapy with bevacizumab
Explanation: ***Retained 1p/19q codeletion predicts continued chemosensitivity to PCV regimen***
- The preservation of **1p/19q codeletion** in a recurrent tumor is the strongest predictor of clinical response to alkylating chemotherapy, specifically the **PCV (Procarbazine, Lomustine, Vincristine)** regimen.
- While the tumor shows histological progression, the underlying molecular subtype remains an **oligodendroglioma**, which generally carries a better prognosis and higher chemosensitivity than non-codeleted gliomas.
*The tumor has progressed to anaplastic oligodendroglioma requiring combined chemoradiation with temozolomide and RT*
- While the histology suggests a higher grade, the standard of care for 1p/19q codeleted tumors frequently favors **PCV** over **Temozolomide** due to more robust long-term survival data from clinical trials like RTOG 9402.
- Grading alone does not dictate management as much as the **molecular profile** does in modern neuro-oncology guidelines.
*CDKN2A/B deletion indicates transformation to glioblastoma requiring maximal therapy*
- Under the current WHO classification, **glioblastoma** is defined as an **IDH-wildtype** tumor; since this tumor has an **IDH1 mutation**, it cannot be classified as a glioblastoma.
- **CDKN2A/B homozygous deletion** is a marker of high-grade malignancy (WHO Grade 4) in IDH-mutant astrocytomas, but its presence in an **oligodendroglioma** does not change the lineage-defining 1p/19q status.
*Loss of IDH1 mutation suggests new primary tumor requiring re-resection only*
- **IDH1 mutations** are early, trunk events in gliomagenesis and are almost never
Question 8: A 55-year-old man presents with progressive supranuclear gaze palsy, axial rigidity, and frequent falls. MRI shows midbrain atrophy with hummingbird sign. He dies 7 years later. Autopsy reveals globose neurofibrillary tangles in the basal ganglia and brainstem. Tau immunostaining shows 4-repeat tau predominance. His brother had similar symptoms. Genetic testing reveals a MAPT mutation. How does this change the pathogenic understanding and potential therapeutic approach?
A. It suggests prion-like propagation requiring anti-aggregation compounds
B. It demonstrates autoimmune etiology requiring immunosuppression
C. It reveals mitochondrial dysfunction requiring coenzyme Q10 supplementation
D. It confirms primary tauopathy amenable to tau-directed antisense oligonucleotide therapy (Correct Answer)
E. It indicates concurrent alpha-synuclein pathology requiring dual-target therapy
Explanation: ***It confirms primary tauopathy amenable to tau-directed antisense oligonucleotide therapy***
- The presence of **MAPT mutations** and **4-repeat (4R) tau** predominance confirms that tau dysfunction is the primary driver of the neurodegenerative process in this **Progressive Supranuclear Palsy (PSP)** phenotype.
- Targeting the underlying genetic cause with **antisense oligonucleotides (ASOs)** can reduce the expression of toxic tau protein, offering a disease-modifying approach rather than just symptomatic relief.
*It suggests prion-like propagation requiring anti-aggregation compounds*
- While **prion-like seeding** occurs in tauopathies, the discovery of a **MAPT mutation** specifically points to a genetic production error rather than isolated misfolding propagation.
- **Anti-aggregation compounds** are a general strategy, but they do not address the primary genetic driver identified by the mutation in this specific case.
*It demonstrates autoimmune etiology requiring immunosuppression*
- **PSP** and related **tauopathies** are degenerative proteinopathies, not autoimmune conditions, and show no response to **immunosuppressive therapy**.
- The **hummingbird sign** and **globose tangles** are classic markers of protein deposition, not inflammatory-mediated demyelination or vasculitis.
*It reveals mitochondrial dysfunction requiring coenzyme Q10 supplementation*
- Although some **mitochondrial deficit** is seen in neurodegeneration, it is a downstream effect and not the primary cause identified by a **MAPT mutation**.
- **Coenzyme Q10** has failed to show significant disease-modifying efficacy in clinical trials for primary tauopathies like **PSP**.
*It indicates concurrent alpha-synuclein pathology requiring dual-target therapy*
- The **MAPT mutation** and **4R tau** findings are specific to tauopathies; **alpha-synuclein** is the hallmark of synucleinopathies like **Parkinson’s disease** or **Multiple System Atrophy (MSA)**.
- Clinical features like the **hummingbird sign** (midbrain atrophy) and **axial rigidity** without resting tremors strongly favor a pure tau pathology over a dual-pathology state.
Question 9: A 70-year-old man with progressive dementia undergoes autopsy. Microscopy shows neuritic plaques and neurofibrillary tangles meeting criteria for Alzheimer disease (AD). However, sections also reveal Lewy bodies in the substantia nigra and cortex, moderate atherosclerosis with old lacunar infarcts, and TDP-43 positive inclusions in the hippocampus. He had no parkinsonian features clinically. What is the most appropriate neuropathologic interpretation?
A. Alzheimer disease with multiple contributing pathologies (mixed dementia) (Correct Answer)
B. Dementia with Lewy bodies with concurrent Alzheimer pathology
C. Vascular dementia with incidental Alzheimer changes
D. Frontotemporal dementia with secondary Alzheimer pathology
E. Primary age-related tauopathy with multiple comorbidities
Explanation: ***Alzheimer disease with multiple contributing pathologies (mixed dementia)***
- The presence of **neuritic plaques** and **neurofibrillary tangles** meeting AD criteria identifies Alzheimer's as the primary pathology, but the coexistence of **vascular**, **Lewy body**, and **TDP-43** changes defines mixed dementia.
- In the elderly, it is increasingly common to find multiple concurrent neurodegenerative processes, which collectively contribute to the clinical presentation of **progressive dementia**.
*Dementia with Lewy bodies with concurrent Alzheimer pathology*
- **Dementia with Lewy bodies (DLB)** requires clinical features such as **visual hallucinations** or **parkinsonism**, which were specifically noted as absent in this patient.
- While **Lewy bodies** were present, their occurrence alongside dominant AD pathology and other changes is better categorized under **mixed dementia** pathology.
*Vascular dementia with incidental Alzheimer changes*
- **Vascular dementia** is usually identified when ischemic changes are the primary drivers; here, the patient met full pathologic criteria for **Alzheimer Disease**.
- **Lacunar infarcts** and **atherosclerosis** in this context are considered contributing factors rather than the singular cause of the patient's decline.
*Frontotemporal dementia with secondary Alzheimer pathology*
- **Frontotemporal dementia (FTD)** typically presents with early changes in **personality**, **behavior**, or **language**, which did not match this patient's clinical history.
- While **TDP-43** inclusions are seen in variants of FTD, in an 70-year-old with AD, they are often a regional comorbid finding called **LATE** (Limbic-predominant Age-related TDP-43 Encephalopathy).
*Primary age-related tauopathy with multiple comorbidities*
- **Primary age-related tauopathy (PART)** is characterized by **neurofibrillary tangles** in the absence of significant **amyloid-beta (neuritic) plaques**.
- Since this patient met formal AD criteria (which includes neuritic plaques), **PART** is an incorrect diagnosis for the underlying tauopathy.
Question 10: A 42-year-old woman presents with behavioral changes, memory loss, and myoclonus. MRI shows cortical ribboning and T2 hyperintensity in the caudate and putamen. EEG shows periodic sharp wave complexes. CSF 14-3-3 is elevated, but real-time quaking-induced conversion (RT-QuIC) is negative. PRNP gene sequencing reveals E200K mutation. Her mother died of similar symptoms at age 45. What feature distinguishes this case from sporadic disease?
A. Longer disease duration with slower progression
B. Younger age of onset and positive family history with genetic mutation (Correct Answer)
C. Absence of spongiform changes on brain biopsy
D. Negative RT-QuIC despite elevated 14-3-3 protein
E. Presence of PrP amyloid plaques in cerebellum
Explanation: ***Younger age of onset and positive family history with genetic mutation***
- The presence of the **E200K mutation** in the **PRNP gene** and a mother affected by similar symptoms at age 45 confirms **familial Creutzfeldt-Jakob disease (fCJD)**.
- Inherited forms typically present at a **younger age** (early 40s to 50s) compared to sporadic CJD, which usually affects patients in their late 60s.
*Longer disease duration with slower progression*
- Both sporadic and **familial CJD** (especially the E200K variant) typically follow a **rapidly progressive** course leading to death within months.
- Only rare genetic prion diseases, like **Gerstmann-Sträussler-Scheinker (GSS)** syndrome, characteristically show a significantly longer disease duration.
*Absence of spongiform changes on brain biopsy*
- **Spongiform degeneration**, consisting of small vacuoles in the gray matter, is the hallmark pathologic feature of **all forms of CJD**, including familial types.
- The absence of these changes would argue against a diagnosis of **transmissible spongiform encephalopathy**.
*Negative RT-QuIC despite elevated 14-3-3 protein*
- While **RT-QuIC** is highly sensitive for sporadic CJD, its sensitivity can vary in **familial cases**; however, a negative result is an assay limitation, not a defining distinguishing feature of the etiology.
- Both **14-3-3 protein** and **RT-QuIC** are diagnostic markers used to support the diagnosis across different subtypes of prion disease.
*Presence of PrP amyloid plaques in cerebellum*
- **Amyloid plaques** containing prion protein are more commonly associated with **vCJD** or **GSS**, whereas E200K fCJD often lacks these plaques.
- The classic **E200K phenotype** closely mimics the sporadic form's pathology, focusing on **vacuolation** and **astrogliosis** rather than plaque formation.
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