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Dementia
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1 Last Minute Review 2 Alzheimer Disease 3 Frontotemporal Dementia 4 Lewy Body & Parkinson Dementia 5 Vascular Cognitive Impairment 6 Rapidly Progressive Dementias 7 Reversible & Secondary Dementias 8 Mild Cognitive Impairment & Dementia Workup 9 Behavioral & Psychiatric Features
Clinical › Dementia

Reversible & Secondary Dementias

Reversible & Secondary Dementias

What Do You Need to Know?

  • NPH classic triad — gait apraxia (first & most responsive to treatment), subcortical dementia, urinary incontinence; Evans index >0.3; lumbar tap test improves gait → VP shunt
  • B12 deficiency — subacute combined degeneration + cognitive decline; methylmalonic acid is the most sensitive marker (elevated even when B12 is borderline normal)
  • Hypothyroidism — most common endocrine cause of reversible dementia; always check TSH in every dementia workup
  • Hashimoto encephalopathy (SREAT) — high TPO antibodies, subacute cognitive decline ± seizures/myoclonus, dramatically steroid-responsive; diagnosis of exclusion
  • Neurosyphilis — CSF VDRL is highly specific (~100%) but insensitive (~50%) — a positive CSF VDRL essentially confirms neurosyphilis. CSF FTA-ABS is highly sensitive; a negative CSF FTA-ABS effectively rules out neurosyphilis. FTA-ABS can be false-positive from peripheral blood contamination. Treat with IV penicillin G
  • Depression pseudodementia — patient complains of memory loss (vs. anosognosia in AD), gives “I don’t know” answers, mood symptoms precede cognition → treat depression and cognition improves
  • Medication-induced — anticholinergics are the biggest culprit; always review medication list before diagnosing neurodegenerative dementia
🚩 Don’t Miss — Test-Day Priorities
  • Give IV thiamine BEFORE glucose: in any suspected Wernicke encephalopathy (alcoholic, bariatric, hyperemesis gravidarum) — glucose first precipitates/worsens Wernicke. Triad = ophthalmoplegia + ataxia + confusion; untreated → irreversible Korsakoff amnesia with confabulation.
  • NPH = ventriculomegaly out of proportion to atrophy: Evans index >0.3, callosal angle <90°, DESH sign; lumbar tap test improvement in gait → predicts shunt response. Gait apraxia comes first and responds best; incontinence comes last and responds least.
  • B12 deficiency — check MMA + homocysteine: both elevated even when serum B12 is borderline normal; classic picture = subacute combined degeneration + sensorimotor neuropathy + megaloblastic anemia + dementia ± glossitis; treat with IM cobalamin.
  • CSF VDRL vs FTA-ABS: CSF VDRL is highly specific (~100%) but insensitive (~50%) — positive essentially confirms neurosyphilis. CSF FTA-ABS is sensitive — negative rules it out. Treat with IV penicillin G for 10–14 days; never substitute with benzathine PCN.
  • SREAT (Hashimoto encephalopathy): subacute encephalopathy ± seizures, myoclonus, stroke-like episodes; high anti-TPO/Tg antibodies; dramatically steroid-responsive. Beware: anti-TPO is common in elderly euthyroid women — confirm with steroid response before attributing cognitive decline to SREAT.
  • Autoimmune encephalitis mimicking dementia: LGI1 → older man + faciobrachial dystonic seizures + hyponatremia (highly treatable, immunotherapy-responsive); NMDAR → younger woman + psychiatric + dyskinesias + screen for ovarian teratoma; CASPR2 → Morvan syndrome. Send paired serum + CSF panel.
  • Medication review & deprescribing: anticholinergics (oxybutynin, diphenhydramine, TCAs), benzodiazepines, opioids, anticonvulsants (topiramate, phenobarbital), metoclopramide, Z-drugs — use STOPP-START / Beers criteria. Always exhaust med review BEFORE diagnosing a neurodegenerative dementia.
  • Pseudodementia clues: patient complains of memory loss (vs anosognosia in AD), answers “I don’t know” rather than confabulating, recent/abrupt onset, prominent neurovegetative symptoms, prior psychiatric history → treat depression and cognition improves.
  • Chronic subdural in the elderly anticoagulated patient: can present as subacute “dementia” without clear trauma history; non-contrast CT or MRI is mandatory; surgical drainage / burr hole / MMA embolization is curative.
  • AAN core/common dementia workup: medication review, depression/delirium/sleep screen, CBC, CMP, TSH, B12, and structural neuroimaging (MRI > CT). Add RPR/VDRL, HIV, inflammatory/autoimmune labs, CSF, EEG, and genetic tests when history, age, tempo, exam, or risk factors support them — per AAN 2001 (reaffirmed), routine syphilis (and HIV) screening is not justified without risk factors or suggestive evidence. Expand aggressively for early-onset or rapidly progressive: folate/MMA/homocysteine, ANA, ESR/CRP, paraneoplastic + autoimmune encephalitis panels, ceruloplasmin (young → Wilson), heavy metals, ammonia, CSF including Aβ42/p-tau biomarkers and 14-3-3/RT-QuIC if prion suspected.
🔍 Buzzwords & Pathognomonic FindingsClinical · Workup / labs · Treatment
Clinical phenotype
  • Magnetic gait, “wet, wacky, wobbly” → Normal pressure hydrocephalus (NPH)
  • Ophthalmoplegia + ataxia + confusion in alcoholic / bariatric / hyperemesis → Wernicke encephalopathy
  • Anterograde amnesia + confabulation after untreated Wernicke → Korsakoff syndrome
  • Frontal disinhibition + delusions of grandeur + Argyll Robertson pupil → General paresis (neurosyphilis)
  • Sensory ataxia + lightning pains + Charcot joints → Tabes dorsalis (neurosyphilis)
  • Older man with faciobrachial dystonic seizures + hyponatremia + cognitive decline → LGI1 autoimmune encephalitis
  • Young woman with psychiatric symptoms + orofacial dyskinesias + autonomic instability → Anti-NMDAR encephalitis (screen for ovarian teratoma)
  • Subcortical executive dysfunction + apathy in advanced HIV/AIDS → HIV-associated neurocognitive disorder (HAND) / AIDS dementia complex
  • Myxedema facies + bradycardia + delayed-relaxation (“hung-up”) reflexes + cognitive slowing → Hypothyroid dementia
  • Patient complains of memory loss + says “I don’t know” + neurovegetative symptoms → Depressive pseudodementia
  • Subacute dementia in elderly anticoagulated patient after minor fall → Chronic subdural hematoma
  • Insomnia + autonomic dysfunction + ataxia in mid-life (Italian/familial) → Fatal familial insomnia (prion) — consider in atypical RPD
Workup / labs / imaging
  • Elevated MMA + homocysteine with borderline serum B12 → B12 deficiency
  • Ventriculomegaly out of proportion to atrophy + Evans index >0.3 + callosal angle <90° + DESH sign → NPH
  • Positive CSF VDRL (highly specific) / negative CSF FTA-ABS rules out → Neurosyphilis
  • High anti-TPO/anti-thyroglobulin antibodies + encephalopathy ± myoclonus → SREAT / Hashimoto encephalopathy
  • Medial temporal FLAIR hyperintensity + PET temporal hypermetabolism → Limbic / autoimmune encephalitis
  • Asterixis + triphasic waves on EEG → Hepatic (or uremic) encephalopathy
  • Low ceruloplasmin + Kayser-Fleischer rings in young patient with cognitive/movement change → Wilson disease
  • Crescentic extra-axial collection on CT, often mixed density, midline shift in elderly → Chronic subdural hematoma
  • STOP-BANG positive + AHI elevated on polysomnography in “dementia” patient → OSA-related cognitive impairment
  • CSF Aβ42 low + p-tau high → Underlying Alzheimer pathology (helps rule in AD when picture is ambiguous)
Treatment / pearls
  • IV thiamine BEFORE glucose → Wernicke encephalopathy (glucose-first precipitates the syndrome)
  • IM cobalamin replacement → B12 deficiency (oral can work but IM if neuro symptoms)
  • IV penicillin G × 10–14 days (never benzathine PCN alone) → Neurosyphilis
  • Levothyroxine replacement → Hypothyroid dementia; high-dose steroids → SREAT (dramatic response is part of the diagnosis)
  • Ventriculoperitoneal (VP) shunt after positive tap test → NPH (gait responds best, incontinence least)
  • Surgical evacuation / burr hole / middle meningeal artery embolization → Chronic subdural hematoma
  • Antiretroviral therapy (ART) + treat opportunistic infections → HAND / AIDS dementia complex
  • IVIG / high-dose steroids / rituximab; remove teratoma if present → Autoimmune encephalitis (NMDAR, LGI1, CASPR2)
  • CPAP therapy → OSA-related reversible cognitive impairment
  • Deprescribe anticholinergics / benzodiazepines / opioids (STOPP-START / Beers) → Medication-induced cognitive impairment
  • Treat the depression (SSRI ± psychotherapy ± ECT) → Pseudodementia — cognition recovers as mood improves
  • Lactulose + rifaximin → Hepatic encephalopathy; chelation (penicillamine, trientine, zinc) → Wilson disease
Normal Pressure Hydrocephalus (NPH)

Classic Triad

Feature Details Board Yield
Gait apraxia Magnetic gait (feet stuck to floor), broad-based, short shuffling steps, difficulty initiating gait First symptom to appear & most responsive to shunting
Dementia Subcortical pattern — psychomotor slowing, executive dysfunction, apathy; memory less impaired than AD Cortical features (aphasia, agnosia) argue against NPH
Urinary incontinence Urinary urgency early; frank incontinence late; last to appear, least responsive to treatment Full triad present in only ~50–60% of cases

Mnemonic: “Wet, Wacky, and Wobbly” — but gait (“wobbly”) is the dominant feature

Imaging & Diagnosis

  • Ventriculomegaly out of proportion to sulcal atrophy — distinguishes NPH from ex vacuo hydrocephalus (where sulci are widened proportionally)
  • Evans index = maximum width of frontal horns ÷ maximum internal diameter of skull at same level; >0.3 = ventriculomegaly
  • DESH sign (Disproportionately Enlarged Subarachnoid-space Hydrocephalus) — tight high-convexity sulci + dilated Sylvian fissures on MRI; strong predictor of shunt responsiveness
  • Periventricular T2/FLAIR hyperintensity — transependymal CSF flow (not always present)
  • Aqueductal flow void on MRI — hyperdynamic CSF flow through the aqueduct

Diagnostic Testing

Test Method Positive Result
Lumbar tap test (Miller Fisher test) Remove 30–50 mL CSF via LP Gait improvement within 30–60 min (video gait analysis before and after); sensitivity ~50–60%, specificity >90%
Extended lumbar drainage Continuous CSF drainage via lumbar catheter over 72 hrs Higher sensitivity (~80%) than single tap; used when tap test equivocal
CSF infusion test Measure CSF outflow resistance Resistance >18 mmHg/mL/min predicts shunt response

Treatment

  • VP shunt (ventriculoperitoneal) — definitive treatment; programmable valves preferred
  • Predictors of good shunt response: gait-predominant symptoms, known etiology (post-SAH, post-meningitic), short symptom duration, positive tap test, DESH on MRI
  • Complications: subdural hematoma/hygroma, infection, over-drainage, shunt malfunction
  • ETV (endoscopic third ventriculostomy) — alternative in selected cases (especially secondary/obstructive forms)
💎 Board Pearl
  • NPH vs. Parkinson disease: both have gait disturbance, but NPH gait is broad-based and “magnetic” (feet glued to floor) while PD gait is narrow-based with festination. NPH does NOT have resting tremor or rigidity.
  • The tap test has LOW sensitivity (~50%) but HIGH specificity (>90%). A negative tap test does NOT rule out NPH — proceed to extended lumbar drainage if clinical suspicion is high.
  • Opening pressure in NPH is normal — hence the name “normal pressure” hydrocephalus. The pathology is impaired CSF absorption, not raised ICP.
Metabolic & Nutritional Causes
Deficiency Neurological Syndrome Key Lab Board-Relevant Details
Vitamin B12 Subacute combined degeneration (dorsal columns + corticospinal tracts) + cognitive decline + megaloblastic anemia Methylmalonic acid (MMA) — most sensitive; homocysteine also elevated Serum B12 can be borderline normal → always check MMA. Nitrous oxide abuse causes acute B12 inactivation. Neurologic damage may be irreversible if treatment delayed
Thiamine (B1) Wernicke encephalopathy (acute: confusion, ataxia, ophthalmoplegia) → Korsakoff syndrome (chronic: anterograde > retrograde amnesia, confabulation) Erythrocyte transketolase (rarely measured); clinical diagnosis Always give thiamine BEFORE glucose in malnourished patients — glucose metabolism consumes thiamine and can precipitate Wernicke. MRI: symmetric T2/FLAIR hyperintensity of mammillary bodies, periaqueductal gray, medial thalami, and tectal plate; mammillary body atrophy chronically; contrast enhancement of mammillary bodies is highly suggestive
Folate Cognitive decline + megaloblastic anemia (similar to B12 but NO subacute combined degeneration) Serum folate, RBC folate Folate supplementation can mask B12 deficiency by correcting anemia while neurologic damage progresses — always check B12 alongside folate
Niacin (B3) Pellagra — the 3 D’s: Diarrhea, Dermatitis, Dementia (+ Death if untreated) Urinary N-methylnicotinamide (low) Associated with alcoholism, carcinoid syndrome (tryptophan diverted to serotonin), isoniazid use, Hartnup disease
Copper Myelopathy mimicking B12 deficiency (dorsal column + corticospinal tract) + cognitive impairment Serum copper & ceruloplasmin (both low) Caused by excess zinc supplementation or gastric bypass surgery; zinc induces metallothionein in enterocytes which sequesters copper
💎 Board Pearl
  • B12 vs. folate deficiency: both cause megaloblastic anemia, but only B12 causes subacute combined degeneration (myelopathy). MMA is elevated in B12 deficiency only; homocysteine is elevated in both.
  • Copper deficiency mimics B12 deficiency on MRI (dorsal column T2 hyperintensity) — if a patient has a “B12-deficiency” picture but normal B12/MMA, check copper and zinc levels.
  • Wernicke encephalopathy is a clinical diagnosis. The classic triad (confusion, ophthalmoplegia, ataxia) is present in only ~10–16% of cases. Always treat empirically with high-dose IV thiamine when suspected.
Endocrine Causes
Condition Mechanism Key Features Diagnosis
Hypothyroidism Slowed neuronal metabolism, reduced cerebral perfusion Most common endocrine cause of reversible dementia; psychomotor slowing, apathy, depression; may mimic AD in elderly TSH (elevated), free T4 (low)
Addison disease Cortisol deficiency → fatigue, confusion, delirium Hypotension, hyperpigmentation, hyponatremia, hyperkalemia Morning cortisol, ACTH stimulation test
Hyperparathyroidism / Hypercalcemia Elevated Ca disrupts neuronal excitability and neurotransmission “Stones, bones, groans, thrones, and psychiatric overtones” — cognitive decline, depression, psychosis Serum calcium, PTH, ionized calcium
Hepatic encephalopathy Ammonia → astrocyte swelling, glutamine accumulation, cerebral edema Asterixis, confusion, sleep-wake reversal; chronic form → progressive cognitive impairment; T1 hyperintensity in globus pallidus (manganese deposition) Ammonia (elevated but poorly correlates with severity), LFTs
Uremic encephalopathy Accumulation of uremic toxins (urea, guanidine compounds) Asterixis, myoclonus, seizures, cognitive decline; dialysis disequilibrium syndrome after rapid correction BUN, creatinine, GFR
Clinical Pearl
  • TSH should be part of every dementia workup — hypothyroidism is common in the elderly and easily treatable. Even subclinical hypothyroidism can contribute to cognitive decline.
  • Hepatic encephalopathy can cause chronic subclinical cognitive impairment (minimal hepatic encephalopathy) detectable only on psychometric testing — suspect it in any patient with cirrhosis and subtle cognitive complaints.
Infectious Causes
Infection Cognitive Syndrome Key Diagnostic Findings Treatment
HIV-associated neurocognitive disorder (HAND) Subcortical dementia — psychomotor slowing, executive dysfunction, apathy; ranges from asymptomatic neurocognitive impairment → mild → HIV-associated dementia (HAD) CD4 typically <200 in HAD; MRI: periventricular/subcortical white matter changes, atrophy; CSF: HIV viral load cART with CNS-penetrating agents; HAND has decreased markedly since cART era
Neurosyphilis General paresis (dementia, personality change, psychosis) — occurs 10–25 years after primary infection; tabes dorsalis (dorsal column degeneration) CSF VDRL — highly specific (~100%) but insensitive (~50%); a positive CSF VDRL essentially confirms neurosyphilis. CSF FTA-ABS — highly sensitive; a negative CSF FTA-ABS effectively rules out neurosyphilis (can be false-positive from peripheral blood contamination); CSF pleocytosis, elevated protein IV penicillin G × 10–14 days; follow with serum RPR titers; repeat LP at 6 months to confirm CSF cell count normalization (most sensitive response marker); CSF VDRL may remain positive for years despite cure
Whipple disease Cognitive decline + GI symptoms (diarrhea, weight loss, arthralgias); CNS involvement in 10–40% PAS-positive macrophages on small bowel biopsy; oculomasticatory myorhythmia (pathognomonic); CSF Tropheryma whipplei PCR IV ceftriaxone × 2 weeks → TMP-SMX × 1 year; relapses common
Chronic meningitis (TB, fungal) Subacute cognitive decline + headache + cranial neuropathies; basilar meningitis pattern TB: CSF lymphocytic pleocytosis, low glucose, high protein, AFB smear/culture, adenosine deaminase. Fungal: CSF cryptococcal antigen, India ink, culture TB meningitis: 2 months RIPE (induction) → 7–10 months INH/RIF (continuation; total 9–12 months); adjunctive steroids reduce mortality. Crypto: amphotericin B + flucytosine → fluconazole
PML (Progressive Multifocal Leukoencephalopathy) Rapidly progressive multifocal white matter disease → cognitive decline, hemiparesis, visual field cuts, ataxia JC virus (CSF PCR); MRI: multifocal, asymmetric, non-enhancing white matter lesions (NO mass effect); immunosuppression (HIV, natalizumab, rituximab) Restore immune function (stop immunosuppressant, start cART); no specific antiviral therapy
💎 Board Pearl
  • Oculomasticatory myorhythmia is pathognomonic for Whipple disease — pendular convergent nystagmus synchronous with jaw contractions. If you see this description on a board question, the answer is Whipple.
  • CSF VDRL vs. FTA-ABS: CSF VDRL is highly specific (~100%) but insensitive (~50%) — a positive CSF VDRL essentially confirms neurosyphilis. CSF FTA-ABS is highly sensitive; a negative CSF FTA-ABS effectively rules out neurosyphilis. FTA-ABS can be false-positive from peripheral blood contamination.
  • PML does NOT enhance with gadolinium (unless immune reconstitution is occurring — IRIS). Non-enhancing, asymmetric, multifocal white matter lesions in an immunosuppressed patient = PML until proven otherwise.
Autoimmune & Inflammatory Causes
Condition Key Features Diagnostic Markers Treatment
Hashimoto encephalopathy / SREAT Subacute cognitive decline, seizures, myoclonus, stroke-like episodes, tremor; relapsing-remitting or progressive; often in women with known thyroid disease Markedly elevated anti-TPO antibodies (anti-thyroglobulin less specific); thyroid function may be normal, hypo, or hyper; EEG: diffuse slowing; MRI often normal Dramatically steroid-responsive (hence “SREAT” = Steroid-Responsive Encephalopathy Associated with autoimmune Thyroiditis); IVIg/PLEX for refractory cases
Neurosarcoidosis Cranial neuropathies (facial nerve most common), hypothalamic dysfunction, cognitive impairment, seizures; leptomeningeal enhancement Serum ACE has low sensitivity (~25–55%); CSF ACE can support diagnosis but also limited sensitivity; chest CT (bilateral hilar lymphadenopathy); gadolinium MRI shows leptomeningeal/pachymeningeal enhancement; tissue biopsy (non-caseating granulomas) is definitive; CSF: lymphocytic pleocytosis, elevated protein Corticosteroids; steroid-sparing agents (methotrexate, azathioprine, infliximab)
CNS vasculitis (PACNS) Headache + multifocal neurologic deficits + cognitive decline; progressive or relapsing CSF abnormal in ~90% (lymphocytic pleocytosis, elevated protein); angiography insensitive and non-specific (~40–90% sensitivity), classic beading pattern (alternating stenosis/dilation); brain + leptomeningeal biopsy is gold standard; ESR/CRP may be normal Cyclophosphamide + steroids; distinguish from reversible cerebral vasoconstriction syndrome (RCVS)
Autoimmune encephalitis Subacute cognitive decline + psychiatric symptoms + seizures; varies by antibody type Anti-NMDAR (young women, ovarian teratoma), anti-LGI1 (faciobrachial dystonic seizures, hyponatremia), anti-CASPR2, anti-AMPAR, anti-GABAB Immunotherapy (steroids, IVIg, PLEX) + tumor removal if paraneoplastic

Autoimmune Encephalitis — Key Antibodies

Antibody Typical Patient Distinguishing Features Tumor Association
Anti-NMDAR Young women Psychiatric symptoms → seizures → movement disorders (orofacial dyskinesias) → autonomic instability → decreased consciousness Ovarian teratoma in ~40–50% of adult women; lower in adolescents, rare in children/men
Anti-LGI1 Older men Faciobrachial dystonic seizures (pathognomonic), hyponatremia, mesial temporal T2 signal Rare
Anti-CASPR2 Older men Morvan syndrome (encephalopathy + neuromyotonia + dysautonomia + insomnia), neuropathic pain Thymoma
Anti-AMPAR Older women Limbic encephalitis, prominent psychiatric features, relapses common Lung, breast, thymus
Anti-GABAB Older adults Limbic encephalitis with prominent seizures SCLC (~50%)
💎 Board Pearl
  • Hashimoto encephalopathy is a diagnosis of exclusion. Anti-TPO antibodies are common in the general population (~10%) — their presence alone does not confirm the diagnosis. The key is: subacute encephalopathy + high TPO + exclusion of other causes + dramatic steroid response.
  • Faciobrachial dystonic seizures (FBDS) are pathognomonic for anti-LGI1 encephalitis. Brief (<3 sec) unilateral arm/face contractions, often refractory to AEDs but responsive to immunotherapy. They frequently precede full limbic encephalitis — early immunotherapy may prevent cognitive decline.
  • PACNS vs. RCVS: PACNS is progressive/relapsing with inflammatory CSF; RCVS presents with thunderclap headache, has normal CSF, and resolves within 3 months. Beading on angiography can be seen in both.
Medication-Induced Cognitive Impairment
Drug Class Examples Mechanism / Notes
Anticholinergics Diphenhydramine, oxybutynin, tricyclic antidepressants, benztropine, first-generation antipsychotics Biggest culprit — block muscarinic receptors in hippocampus and cortex; cumulative anticholinergic burden correlates with dementia risk; Beers criteria flag these in elderly
Benzodiazepines Lorazepam, diazepam, clonazepam, alprazolam GABAA enhancement → sedation, anterograde amnesia; long-acting agents worse in elderly; controversial association with long-term dementia risk
Opioids Morphine, oxycodone, fentanyl, tramadol Central sedation, executive dysfunction; elderly especially susceptible; delirium risk
Anticonvulsants Topiramate (“dopamax”), phenobarbital, valproate Topiramate causes word-finding difficulty, psychomotor slowing; phenobarbital causes sedation; valproate → reversible parkinsonism and cognitive slowing in elderly
Chemotherapy Methotrexate, cisplatin, 5-FU, cytarabine “Chemo brain” — cognitive dysfunction during/after chemotherapy; may persist months to years; methotrexate leukoencephalopathy (especially intrathecal)
Others Lithium, digoxin, beta-blockers (lipophilic), corticosteroids, H2 blockers (cimetidine) Often overlooked; polypharmacy in elderly amplifies risk
Clinical Pearl
  • Always perform a medication reconciliation before diagnosing a neurodegenerative dementia. Use the Anticholinergic Cognitive Burden (ACB) Scale to quantify anticholinergic load — a total score ≥3 significantly increases cognitive impairment risk.
  • Topiramate is the anticonvulsant most likely to cause cognitive side effects — word-finding difficulty is so common it earned the nickname “dopamax.” Consider switching to an alternative if cognitive complaints develop.
Depression Pseudodementia

Pseudodementia vs. True Dementia

Feature Depression Pseudodementia Alzheimer Disease
Onset Acute/subacute, dateable onset Insidious, gradual (family may not recall exact onset)
Awareness of deficits Patient complains of memory loss, exaggerates disability Anosognosia — patient unaware of or minimizes deficits
Typical answers “I don’t know” answers; doesn’t try Near-miss confabulatory answers; tries but fails
Mood vs. cognition Mood symptoms precede cognitive symptoms Cognitive symptoms precede mood changes
Effort on testing Effort-dependent poor performance; inconsistent deficits Genuine effort with consistent deficit pattern
Progression Rapid decline Slow, progressive decline over years
Response to treatment Cognition improves with antidepressant therapy No improvement with antidepressants
History Prior psychiatric history common No prior psychiatric history (typically)
💎 Board Pearl
  • The single most distinguishing feature: In pseudodementia, the patient complains of memory loss (insight preserved); in AD, the patient denies or is unaware of deficits (anosognosia). If the patient is the one bringing up memory concerns, think depression first.
  • Pseudodementia is a risk factor for true dementia — patients who present with depressive pseudodementia have a higher rate of developing AD in subsequent years. Follow these patients longitudinally.
Chronic Subdural Hematoma

Key Features

  • Epidemiology: elderly patients, often on anticoagulants/antiplatelets; minor or forgotten head trauma
  • Pathophysiology: bridging vein tear → slow accumulation of blood in subdural space → membrane formation with neo-vascularization → recurrent micro-hemorrhages
  • Presentation: gradual cognitive decline, personality change, headache, gait instability, focal deficits (hemiparesis); can mimic neurodegenerative dementia or NPH
  • CT appearance: crescent-shaped collection conforming to brain surface; hyperdense (acute), isodense (subacute — easily missed), hypodense (chronic); mixed density suggests re-bleeding
  • MRI: more sensitive than CT, especially for isodense collections and bilateral thin subdurals

Treatment

  • Surgical evacuation — burr hole drainage is standard; craniotomy for organized/septated collections
  • Reverse anticoagulation — correct INR, hold anticoagulants
  • Middle meningeal artery (MMA) embolization — emerging treatment option to reduce recurrence
  • Small, asymptomatic collections — may be observed with serial imaging
Clinical Pearl

An elderly patient on anticoagulation with subacute cognitive decline over weeks should always prompt neuroimaging to rule out chronic subdural hematoma. Isodense subdurals on CT can be easy to miss — look for sulcal effacement, midline shift, or “white matter buckling sign.” When in doubt, get an MRI.

Sleep Disorders & Cognitive Impairment

Obstructive Sleep Apnea (OSA)

  • Mechanism: intermittent hypoxia + sleep fragmentation → hippocampal atrophy, white matter changes, impaired attention/executive function/memory
  • Prevalence: up to 50% of elderly patients with dementia have comorbid OSA
  • Cognitive domains affected: attention, vigilance, executive function, working memory; can mimic or exacerbate neurodegenerative dementia
  • Diagnosis: polysomnography (AHI ≥5 events/hr with symptoms); screening: STOP-BANG questionnaire, Epworth Sleepiness Scale
  • Treatment: CPAP improves attention, executive function, and psychomotor speed; may slow cognitive decline in mild cognitive impairment (MCI)
  • Alzheimer link: OSA increases amyloid-beta deposition (impaired glymphatic clearance during disrupted sleep) → possible modifiable risk factor for AD
💎 Board Pearl
  • OSA is a treatable contributor to cognitive decline — always screen for sleep disorders in the dementia workup. An obese, snoring patient with daytime somnolence and executive dysfunction may have “reversible dementia” from untreated OSA.
  • The glymphatic system clears cerebral metabolic waste (including amyloid-beta) during deep sleep. Sleep disruption from OSA impairs this clearance → increased amyloid deposition. This is why OSA is now considered a modifiable risk factor for Alzheimer disease.
Wilson Disease

Key Features

  • Genetics: autosomal recessive; ATP7B mutation on chromosome 13q; defective copper transport → copper accumulation in liver, brain, cornea, and other tissues
  • Multi-system involvement: hepatic (acute hepatitis, cirrhosis, fulminant hepatic failure), neuropsychiatric, ocular (Kayser-Fleischer rings)
  • Neurologic features: parkinsonism, dystonia, tremor (classic “wing-beating” proximal tremor), dysarthria, ataxia, behavioral/psychiatric changes (personality change, depression, psychosis)

Diagnosis

Test Finding Board-Relevant Detail
Serum ceruloplasmin <20 mg/dL (low) Can be normal in 10–15% of patients — a normal ceruloplasmin does NOT exclude Wilson disease
24-hour urinary copper >100 µg (often >200 in symptomatic patients) Most useful screening test in suspected neurologic Wilson
Serum copper Variably low (total copper); free copper elevated Total serum copper tracks ceruloplasmin (bound fraction)
LFTs Abnormal (transaminitis, synthetic dysfunction) May be the only clue in pre-symptomatic siblings
Slit-lamp exam Kayser-Fleischer (K-F) rings (Descemet membrane copper deposition) ~95% sensitivity in patients with neurologic Wilson; may be absent in purely hepatic presentation
Brain MRI T2 hyperintensity in basal ganglia (especially putamen), thalamus, midbrain; “face of the giant panda” sign in midbrain Panda sign = preserved red nuclei and lateral pars reticulata against T2 bright tegmentum
Genetic testing ATP7B sequencing Confirms diagnosis; useful in screening relatives; >500 known mutations
Liver biopsy Hepatic copper >250 µg/g dry weight Gold standard when diagnosis remains uncertain after non-invasive workup

Treatment

  • Chelation therapy: trientine (preferred — better tolerated) or penicillamine (older agent; risk of paradoxical neurologic worsening, lupus-like syndrome, marrow suppression)
  • Zinc — maintenance therapy; induces metallothionein in enterocytes which sequesters dietary copper
  • Dietary copper restriction — avoid shellfish, liver, nuts, chocolate, mushrooms
  • Lifelong therapy required; discontinuation can precipitate fulminant hepatic failure
  • Liver transplantation — curative for fulminant hepatic failure or end-stage cirrhosis; corrects the underlying enzymatic defect
💎 Board Pearl
  • Any young patient with a movement disorder + psychiatric features + abnormal LFTs should prompt a Wilson disease workup. Symptom onset is typically between ages 5 and 35.
  • The “face of the giant panda” sign on midbrain MRI is highly suggestive but not pathognomonic — preserved red nuclei and lateral substantia nigra appear dark against the T2-bright tegmentum.
  • K-F rings can be absent in purely hepatic Wilson but are present in ~95% of neurologic Wilson cases. Slit-lamp exam by ophthalmology is mandatory.
  • Wing-beating tremor — coarse, proximal, high-amplitude tremor of the shoulders elicited by arm abduction — is a classic neurologic Wilson feature.
Spontaneous Intracranial Hypotension (CSF Leak)

Key Features

  • Pathophysiology: spontaneous spinal CSF leak (often from a meningeal diverticulum, dural tear, or CSF-venous fistula) → reduced CSF volume → brain sagging and traction on pain-sensitive structures
  • Cognitive mimic: can mimic frontotemporal dementia with behavioral changes and frontotemporal brain sagging on imaging — an important reversible cause to recognize
  • Orthostatic headache is the hallmark — worse upright, better supine; may evolve to non-positional headache over time
  • Other features: neck pain/stiffness, nausea, tinnitus, diplopia (CN VI palsy from traction), photophobia, cognitive slowing, decreased level of consciousness in severe cases

Imaging & Diagnosis

  • MRI brain with contrast (SEEPS mnemonic):
    • Subdural fluid collections (typically thin, bilateral hygromas)
    • Enhancement of the pachymeninges (diffuse, smooth, non-nodular)
    • Engorgement of venous structures (dural venous sinuses, pituitary)
    • Pituitary enlargement
    • Sagging of the brain — low-lying cerebellar tonsils, effaced suprasellar/prepontine cisterns, reduced mamillopontine distance
  • Localization of leak: CT myelography (gold standard), dynamic CT myelography, MR myelography, or radionuclide cisternography

Treatment

  • Conservative: bed rest, hydration, caffeine, abdominal binder
  • Epidural blood patch — first-line procedural therapy; often performed empirically at the lumbar level if leak not localized
  • Targeted epidural patch (blood or fibrin glue) at the site of the leak if localized
  • Surgical repair — for refractory cases or identified structural lesions (meningeal diverticulum, CSF-venous fistula)
Clinical Pearl

Any patient presenting with cognitive/behavioral decline + orthostatic headache + brain sagging on MRI should be evaluated for spontaneous intracranial hypotension before being diagnosed with frontotemporal dementia. Diffuse pachymeningeal enhancement is the most useful imaging clue. The condition is reversible with prompt recognition and epidural blood patching.

Screening Workup for Reversible Dementias

Must-Order Labs for Every Dementia Evaluation

Category Test What It Rules Out
Metabolic CBC with differential Megaloblastic anemia (B12/folate), infection
CMP (BUN, creatinine, electrolytes, glucose, calcium, LFTs) Uremia, hepatic encephalopathy, hypercalcemia, hyponatremia, hypoglycemia
Ammonia Hepatic encephalopathy (if liver disease suspected)
Endocrine TSH Hypothyroidism (most important single screening test for reversible dementia)
Free T4 Confirms hypothyroidism if TSH elevated
Nutritional Vitamin B12 B12 deficiency
Methylmalonic acid (MMA) B12 deficiency (order if B12 borderline 200–400 pg/mL)
Folate Folate deficiency
Thiamine (B1) Wernicke-Korsakoff (if alcoholism or malnutrition suspected)
Infectious (risk-stratified, not routine — AAN 2001 reaffirmed) RPR/VDRL Syphilis — order based on risk factors / suggestive features, not routinely (if positive → CSF VDRL/FTA-ABS)
HIV testing HIV-associated neurocognitive disorder — order based on risk factors / young-onset / subcortical pattern, not routinely
Inflammatory ESR, CRP Vasculitis, chronic infection, inflammatory conditions
Anti-TPO antibodies Hashimoto encephalopathy / SREAT (if subacute presentation)
Imaging Brain MRI (or CT if MRI contraindicated) NPH, chronic subdural hematoma, mass lesion, vascular disease, white matter disease
Other Urinalysis UTI (common delirium trigger in elderly, can worsen baseline dementia)
Medication review Drug-induced cognitive impairment (anticholinergics, benzodiazepines, opioids)

Extended Workup (When Indicated)

Test When to Order What It Rules Out
Copper, ceruloplasmin, zinc Myelopathy with cognitive decline; gastric bypass history Copper deficiency, Wilson disease
Heavy metals (lead, mercury, arsenic) Occupational exposure, environmental concerns Heavy metal toxicity
CSF analysis (cells, protein, glucose, cytology, 14-3-3, RT-QuIC) Rapidly progressive dementia, suspicion for CJD, autoimmune, infectious, or neoplastic etiology CJD, autoimmune encephalitis, chronic meningitis, leptomeningeal carcinomatosis
Autoimmune encephalitis panel (serum + CSF) Subacute onset, seizures, psychiatric symptoms, movement disorder Anti-NMDAR, anti-LGI1, anti-CASPR2, anti-AMPAR, anti-GABAB
Paraneoplastic antibodies Cancer history, subacute cerebellar degeneration, limbic encephalitis Anti-Hu, anti-CV2, anti-Ma2, anti-amphiphysin
EEG Fluctuating cognition, seizures, rapidly progressive dementia Non-convulsive status epilepticus, CJD (periodic sharp wave complexes), autoimmune encephalitis
Polysomnography Daytime somnolence, snoring, obesity, witnessed apneas Obstructive sleep apnea
PTH, ionized calcium Elevated serum calcium Hyperparathyroidism
Morning cortisol, ACTH stimulation test Hypotension, hyperpigmentation, electrolyte abnormalities Addison disease
ACE level, chest CT Multi-system disease, cranial neuropathy, leptomeningeal enhancement Neurosarcoidosis
💎 Board Pearl
  • Core/common dementia workup per AAN guidelines: medication review, depression/delirium/sleep screen, CBC, CMP, TSH, B12, and brain imaging (MRI preferred). Add RPR/VDRL, HIV, inflammatory, autoimmune, CSF, EEG, and genetic tests when history, age, tempo, exam, or risk factors support them — per AAN 2001 (reaffirmed), routine syphilis screening is NOT justified without risk factors or suggestive evidence.
  • Reversible causes account for <5% of all dementias in most studies — but they must always be screened for because treatment can dramatically change outcomes. The yield is highest in younger patients (<65) and those with subacute or atypical presentations.
  • A “rapidly progressive dementia” (weeks to months rather than years) demands an aggressive workup including CSF studies, EEG, and autoimmune panels — the differential shifts from neurodegenerative to potentially treatable etiologies (autoimmune encephalitis, CJD, infection, malignancy).
High-Yield Summary Table
Reversible Cause Classic Clue Key Test Treatment
NPH Magnetic gait + dementia + incontinence; ventriculomegaly without proportional atrophy Lumbar tap test; Evans index >0.3 VP shunt
B12 deficiency Subacute combined degeneration + megaloblastic anemia MMA (most sensitive) B12 supplementation (IM or high-dose oral)
Hypothyroidism Psychomotor slowing, weight gain, cold intolerance in elderly TSH Levothyroxine
Neurosyphilis Personality change + Argyll Robertson pupils + CSF pleocytosis CSF VDRL (specific); CSF FTA-ABS (sensitive) IV penicillin G
Hashimoto encephalopathy Subacute encephalopathy + high TPO + thyroid disease Anti-TPO antibodies Corticosteroids (dramatic response)
Chronic SDH Elderly, anticoagulated, subacute cognitive decline CT head (crescent-shaped collection) Surgical evacuation
Depression pseudodementia Patient complains of memory loss; “I don’t know” answers; mood precedes cognition Clinical assessment; neuropsychological testing Antidepressants → cognition improves
Medication-induced Temporal correlation with offending drug; anticholinergic burden Medication reconciliation; ACB scale Discontinue/substitute offending agent
Wernicke-Korsakoff Alcoholism + confusion + ataxia + ophthalmoplegia Clinical diagnosis; MRI: mammillary body changes High-dose IV thiamine (before glucose!)
OSA Obesity, snoring, daytime somnolence, executive dysfunction Polysomnography (AHI ≥5) CPAP
Autoimmune encephalitis Subacute onset, seizures, psychiatric symptoms, young patient Autoimmune encephalitis panel (serum + CSF) Immunotherapy + tumor removal
Hepatic encephalopathy Cirrhosis + asterixis + sleep-wake reversal; T1 bright globus pallidus Ammonia (but poor correlation); clinical diagnosis Lactulose + rifaximin
Wilson disease Young patient with movement disorder + psychiatric features + abnormal LFTs; K-F rings; wing-beating tremor Low ceruloplasmin, elevated 24-hr urinary copper, slit-lamp; MRI “face of the giant panda”; ATP7B sequencing Chelation (trientine or penicillamine), zinc maintenance, copper-restricted diet; liver transplant for fulminant failure
Spontaneous intracranial hypotension (CSF leak) Orthostatic headache + behavioral/cognitive decline; can mimic FTD with brain sagging MRI: pachymeningeal enhancement, brain sagging, subdural collections; CT myelography to localize leak Bed rest/hydration/caffeine; epidural blood patch (empiric or targeted)

References

  1. Clarfield AM. The decreasing prevalence of reversible dementias: an updated meta-analysis. Arch Intern Med. 2003;163(18):2219-2229.
  2. Williams MA, Malm J. Diagnosis and treatment of idiopathic normal pressure hydrocephalus. Continuum (Minneap Minn). 2016;22(2):579-599.
  3. Relkin N, Marmarou A, Klinge P, Bergsneider M, Black PM. Diagnosing idiopathic normal-pressure hydrocephalus. Neurosurgery. 2005;57(3 Suppl):S4-16.
  4. Hashimoto M, Ishikawa M, Mori E, Kuwana N. Diagnosis of idiopathic normal pressure hydrocephalus is supported by MRI-based scheme: a prospective cohort study (SINPHONI-2). Lancet Neurol. 2015;14(6):585-594.
  5. Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.
  6. Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001;56(9):1143-1153.
  7. Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med. 2018;378(9):840-851.
  8. Linnebank M, Moskau S, Semmler A, et al. Antiepileptic drugs interact with folate and vitamin B12 serum levels. Ann Neurol. 2011;69(2):352-359.
  9. Osorio RS, Gumb T, Pirraglia E, et al. Sleep-disordered breathing advances cognitive decline in the elderly. Neurology. 2015;84(19):1964-1971.
  10. Geschwind MD. Rapidly progressive dementia. Continuum (Minneap Minn). 2016;22(2):510-537.
  11. Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015;175(3):401-407.
  12. Killin LOJ, Starr JM, Shiue IJ, Russ TC. Environmental risk factors for dementia: a systematic review. BMC Geriatr. 2016;16(1):175.
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