HIV Parkinsons Neuropsych

Study Notes

Comprehensive Study Notes for MD Psychiatry Exit Examination

PART 1: HIV & NEUROPSYCHIATRY

1.1 EPIDEMIOLOGY AND OVERVIEW

HIV (Human Immunodeficiency Virus) infects approximately 38 million people globally. In India, the estimated prevalence is ~2.3 million. The neuropsychiatric burden of HIV is substantial:

• 50–70% of HIV-positive individuals will develop some form of neuropsychiatric complication over their lifetime
• Neuropsychiatric manifestations may be the presenting feature of HIV infection
• With the advent of combination antiretroviral therapy (cART), the landscape has shifted, severe HAD has decreased, but milder forms of HAND have become more prevalent
• Psychiatric comorbidity worsens HIV outcomes: reduces ART adherence, increases risky behavior, accelerates disease progression

1.2 HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS (HAND)

Box: HAND Classification (Antinori et al., 2007)

Neuropsychological Domains Assessed in HAND

Six domains must be assessed:

1. Learning/Memory, verbal and visual
2. Attention/Working Memory, most commonly impaired
3. Executive Function, planning, cognitive flexibility
4. Speed of Information Processing, psychomotor slowing (hallmark)
5. Language, verbal fluency
6. Motor Skills, fine motor speed, coordination

Key Feature: HAND is a subcortical dementia, psychomotor slowing, personality change, poor concentration, memory retrieval deficits (not encoding). Contrast with Alzheimer's (cortical, aphasia, apraxia, agnosia).

1.3 PATHOPHYSIOLOGY OF HAND

Direct Viral Neurotoxicity

HIV does not directly infect neurons (neurons lack CD4 receptors). Instead:

1. Macrophage/Microglia Reservoir: HIV infects macrophages and microglia in the CNS. These become reservoirs for viral replication.

1. HIV proteins as neurotoxins:
2. gp120 (viral envelope glycoprotein): Binds CXCR4/CCR5 on neurons → calcium influx → excitotoxicity → apoptosis
3. Tat protein: Disrupts blood-brain barrier, induces oxidative stress, activates microglia, dysregulates neurotransmitter systems (dopamine pathway particularly affected)
4. Vpr: Promotes apoptosis
5. gp41: Mitochondrial dysfunction

1. Bystander neurotoxicity: HIV-infected macrophages release cytokines (IL-1β, TNF-α, IL-6), quinolinic acid (NMDA agonist → excitotoxicity), and reactive oxygen species

Immune Activation

• Persistent immune activation even on ART ("inflammaging")
• Chronic microglial activation → neuroinflammation
• CD8+ T-cell infiltration into CNS
• Blood-brain barrier disruption → increased CNS penetration of inflammatory mediators
• The monocyte/macrophage is the central culprit, not the T-cell

CNS Penetration Effectiveness (CPE) Score of ART

Not all ART drugs penetrate the CNS equally. CPE score (0–4 per drug, summed for regimen):

• High CPE: Zidovudine (AZT), Nevirapine, Lopinavir/ritonavir
• Low CPE: Tenofovir, Ritonavir alone
• Target CPE ≥8 for CNS disease

1.4 ASSESSMENT: INTERNATIONAL HIV DEMENTIA SCALE (IHDS)

Box: IHDS: 3 Components

Sensitivity: 74% | Specificity: 54% for HAD

Advantage: Bedside tool, culturally applicable, quick (<5 minutes)

Limitation: Not validated for ANI/MND, misses milder forms

Other assessment tools:

• Montreal Cognitive Assessment (MoCA): General cognitive screen, not HIV-specific
• HIV Dementia Scale (HDS): Older version (Power et al., 1995)
• Brief Neurocognitive Screen (BNCS)
• Formal neuropsychological battery: gold standard but requires trained personnel

1.5 CNS OPPORTUNISTIC INFECTIONS IN HIV

1.5.1 Toxoplasma Encephalitis

Organism: Toxoplasma gondii (intracellular protozoan)

Mechanism: Reactivation of latent cysts (primary infection usually acquired in childhood from cat feces or undercooked meat)

CD4 threshold: Typically <100 cells/μL (most common when <50)

Epidemiology: Most common mass lesion in HIV in developing world

Clinical Features:

• Fever, headache, focal neurological deficits
• Seizures (30%)
• Altered consciousness
• Gradual onset over days-weeks

Neuroimaging:

• CT/MRI: Multiple ring-enhancing lesions, typically at grey-white junction and basal ganglia
• "Target sign" on MRI (central enhancement, ring enhancement, surrounding edema)
• Classic teaching: Bilateral lesions in basal ganglia

Diagnosis:

• Serology: Toxoplasma IgG positive (90–95% of cases, previous exposure)
• CSF: PCR for T. gondii (sensitivity 50–60%)
• Definitive: Brain biopsy (rarely needed if response to empirical treatment)
• Key rule: If IgG negative + classic MRI appearance → consider CNS lymphoma first

Treatment:

• Pyrimethamine + Sulfadiazine + Leucovorin (folinic acid to prevent bone marrow suppression)
• Alternative: Pyrimethamine + Clindamycin (if sulfa allergy)
• Duration: 6 weeks acute, then lifelong secondary prophylaxis
• Clinical response expected by 2 weeks, if no response, biopsy
• Primary prophylaxis: Co-trimoxazole (TMP-SMX) when CD4 <100

1.5.2 Progressive Multifocal Leukoencephalopathy (PML)

Organism: JC virus (John Cunningham virus), polyomavirus

Mechanism: Reactivation of latent JC virus in oligodendrocytes → lytic infection → demyelination

CD4 threshold: Typically <200 cells/μL

Clinical Features:

• Subacute progressive focal neurological deficits
• Cognitive decline
• Visual field defects (posterior leukoencephalopathy)
• NO fever, NO meningismus
• Headache is rare
• Can cause significant personality change (frontal lobe involvement)

Neuroimaging:

• MRI: Non-enhancing (or faint enhancement), T2 hyperintense white matter lesions
• No mass effect, no ring enhancement, distinguishes from toxoplasmosis
• Multifocal lesions predominantly in subcortical white matter
• Posterior-parietal-occipital predominance common

Diagnosis:

• CSF: JC virus PCR (sensitivity 72–92%, specificity 92–99%)
• Biopsy: Diagnostic gold standard, demyelination, enlarged oligodendrocyte nuclei, bizarre astrocytes, absence of inflammatory infiltrate

Treatment:

• No specific treatment for JC virus
• Mainstay: Optimize ART (immune reconstitution)
• IRIS (Immune Reconstitution Inflammatory Syndrome) can worsen PML paradoxically when starting ART
• Prognosis: Poor without immune recovery. With ART, ~50% survive but most with neurological sequelae

1.5.3 Cryptococcal Meningitis

Organism: Cryptococcus neoformans (encapsulated yeast)

CD4 threshold: Typically <100 cells/μL (most common when <50)

Route: Inhalation → pulmonary → hematogenous spread to CNS

High-yield: Polysaccharide capsule resists phagocytosis; capsule visible with India ink stain

Clinical Features:

• Subacute/chronic meningitis, develops over weeks
• Headache (most prominent), fever, malaise
• Meningismus may be ABSENT (poor inflammatory response)
• Elevated intracranial pressure (ICP), may cause vision loss, CN VI palsy
• Papilledema (30%)
• Altered consciousness if severe

CSF Findings:

Diagnosis:

• Serum CrAg excellent screening test in endemic areas (sensitivity >99%)
• India ink: "Halo" appearance, yeast with large clear capsule
• Blood culture positive in 50–70%

Treatment:

• Induction (2 weeks): Amphotericin B deoxycholate + Flucytosine
• Consolidation (8 weeks): Fluconazole 400mg/day
• Maintenance: Fluconazole 200mg/day (lifelong or until CD4 >200 for >6 months)
• ICP management: Serial therapeutic lumbar punctures (drain to <200 mmH2O), NO acetazolamide/steroids/mannitol routinely
• IRIS: Can occur when starting ART; corticosteroids used for severe IRIS

1.5.4 CMV Encephalitis / Retinitis

Organism: Cytomegalovirus (herpesvirus)

CD4 threshold: <50 cells/μL (most immunosuppressed patients)

CMV Retinitis (most common CMV manifestation):

• Painless progressive vision loss
• "Pizza pie" or "ketchup and cheese" fundoscopic appearance
• Retinal hemorrhages and exudates in perivascular distribution
• Treatment: Ganciclovir, Valganciclovir, Cidofovir, Foscarnet

CMV Encephalitis:

• Acute/subacute encephalopathy
• Ventriculoencephalitis pattern on MRI (periventricular enhancement)
• CSF: CMV PCR positive
• Treatment: Ganciclovir IV + Foscarnet (combination for encephalitis)

CMV Polyradiculopathy:

• Lumbosacral polyradiculopathy
• Lower extremity weakness, urinary retention
• CSF: Neutrophilic pleocytosis (unusual, raises CMV suspicion in HIV)

1.5.5 Other CNS OIs

Swipe to compare →

1.6 PSYCHIATRIC DISORDERS IN HIV

1.6.1 Depression in HIV

Prevalence: 30–60% (vs ~10–15% general population)

Why so high?

1. Direct neurobiological effects of HIV (viral proteins, cytokine dysregulation, HPA axis activation)
2. Substance use comorbidity (bidirectional)
3. Psychosocial burden: stigma, discrimination, bereavement, financial stress, illness adjustment
4. ART side effects (particularly efavirenz)
5. Nutritional deficiencies (B12, folate)
6. OI-related factors

Clinical Assessment Challenges:

• Somatic symptoms of depression (fatigue, weight loss, sleep disturbance) overlap with HIV illness itself
• Use psychological/cognitive criteria preferentially:
• Hopelessness, worthlessness, guilt, anhedonia, poor concentration
• PHQ-9 and BDI-II validated in HIV populations

Treatment:

• SSRIs first-line (fluoxetine, escitalopram, sertraline), well-tolerated, favorable drug-drug interaction profile compared to TCAs
• Note: Fluoxetine inhibits CYP2D6 and CYP3A4, check interactions with ART (e.g., ritonavir also inhibits CYP3A4)
• MAOIs: Avoid due to food interactions and ART interactions
• Psychotherapy: CBT and interpersonal therapy (IPT) have evidence base
• Address substance use, high comorbidity
• Depression improves ART adherence when treated, this is a key clinical point

1.6.2 Adjustment Disorder

• Very common at time of HIV diagnosis and disease progression milestones
• Distress disproportionate to, but related to, the stressor (diagnosis, OI development, AID S progression)
• Does not meet criteria for MDD, PTSD, or anxiety disorder
• Treatment: Psychotherapy (supportive, CBT), brief anxiolytics if needed
• Usually resolves within 6 months of stressor removal (but HIV is ongoing stressor)

1.6.3 Mania in HIV: Important High-Yield Topic

Two types:

Type 1, Primary Bipolar Disorder (pre-existing):

• Pre-dates HIV diagnosis or early-stage HIV
• Standard bipolar features
• May be exacerbated by HIV

Type 2, Secondary/HIV-Associated Mania (Late-Stage):

• Emerges in advanced HIV (CD4 <200)
• Called "AIDS mania" or secondary mania
• Typically first episode, no family history of bipolar disorder
• Features:
• Irritability dominant (not euphoria)
• Cognitive impairment prominent (may look like disinhibited dementia)
• Psychomotor agitation
• May progress to HAD
• Mechanism: Direct viral/immune effect on basal ganglia and frontal circuits

ART-Associated Mania:

• Efavirenz is the most notorious, neuropsychiatric effects including vivid dreams, insomnia, psychosis, and mania
• Efavirenz (NNRTI): Acts on dopaminergic and serotonergic systems; CNS side effects in 40–52% of patients
• Usually resolves with switch to alternative ART (e.g., switch to dolutegravir-based regimen)
• Other ART with neuropsychiatric effects: Zidovudine (AZT), headache, anxiety; Didanosine (ddI), peripheral neuropathy, rarely CNS

Treatment of HIV-Associated Mania:

• Valproate preferred (fewer drug interactions, hepatic metabolism compatible with most ART)
• Avoid lithium, renal toxicity, narrow therapeutic window; potential interactions with tenofovir (both nephrotoxic)
• Antipsychotics may be needed, note increased extrapyramidal sensitivity (use atypicals; haloperidol causes marked EPS in HIV patients)
• Address underlying HIV progression

1.6.4 Psychosis in HIV

Prevalence: ~15% lifetime risk (vs 1% general population)

Types:

1. HIV-related psychosis (direct neurological involvement, HAD with psychotic features)
2. Substance-induced psychosis (cannabis, methamphetamine, very common in HIV populations)
3. OI-related psychosis (CNS toxoplasmosis, PML, cryptococcal meningitis presenting with behavioral disturbance)
4. ART-induced psychosis (efavirenz most common)
5. Steroid-induced psychosis (used for PCP pneumonia, IRIS, CNS lymphoma)
6. Primary psychotic illness comorbid with HIV

Clinical approach:

• Rule out OI first (imaging, CSF if needed)
• Rule out substances
• Review ART (especially efavirenz)
• Review other medications (steroids)

Treatment:

• Atypical antipsychotics preferred, less EPS than typicals in HIV patients
• HIV patients are very sensitive to EPS (basal ganglia involvement)
• Clozapine: Use with caution, increased risk of agranulocytosis + HIV itself causes neutropenia
• Olanzapine: Effective but metabolic effects relevant in HIV (already nutritionally compromised)
• Quetiapine: Often used; good for psychosis + sleep disturbance
• Drug interactions: Ritonavir (CYP3A4 inhibitor) increases levels of many antipsychotics

1.6.5 Anxiety Disorders

• Generalized anxiety: Common; often overlaps with adjustment disorder
• PTSD: Very high in HIV populations (sexual trauma/violence as risk factor for HIV acquisition; abuse-related trauma)
• Panic disorder: Can be precipitated by breath-related symptoms (PCP, CMV pneumonitis)
• Treatment: SSRIs, buspirone; benzodiazepines carefully (drug interactions with ritonavir, dramatically increase levels)

1.6.6 Substance Use in HIV

Bidirectional relationship:

• Substance use increases HIV acquisition risk (needle sharing, sexual disinhibition)
• HIV increases substance use risk (stigma, pain, depression, social environment)

Key Substances:

• Injection Drug Use (IDU): Primary HIV transmission route in many settings; opioid use disorder; consider OAMT (opioid agonist maintenance therapy, buprenorphine/methadone)
• Alcohol: Most common; worsens medication adherence, liver disease (especially if HCV co-infected), accelerates neurocognition decline
• Methamphetamine: Particularly neurotoxic in HIV, synergistic damage to dopaminergic system; increases viral replication
• Cannabis: Used for appetite/pain/sleep; smoked cannabis risks pulmonary OIs
• Chemsex: GBMSM-specific; involves crystal meth, mephedrone, GHB/GBL, high-risk sexual behavior, very relevant in HIV

1.7 ART AND PSYCHIATRIC SIDE EFFECTS

Box: ART Neuropsychiatric Side Effects

Efavirenz Mechanism for CNS Effects:

• Agonist at GABA-A receptors (causes drowsiness and unusual dreams)
• Inverse agonist at CB1 receptors (cannabis receptor)
• Inhibits CYP2B6 (its own metabolism), CYP3A4, CYP2C9
• Symptoms typically worst in first 2–4 weeks, improve by 6–8 weeks
• Switch to dolutegravir now first-line in most guidelines, much better CNS profile

1.8 ART ADHERENCE AND PSYCHIATRIC FACTORS

Target adherence: >95% for viral suppression with older agents; newer long-acting injectables allow monthly dosing

Psychiatric barriers to adherence:

1. Active depression, most studied; OR 3.4 for non-adherence
2. Psychosis, grandiosity ("I don't need pills"), paranoia about medications
3. Active substance use, chaotic lifestyle
4. Neurocognitive impairment, forgetting doses (ANI/MND/HAD)
5. PTSD, avoidance of reminders of HIV
6. Adverse effects, efavirenz dream disturbance leads to pill-stopping

Strategies:

• Treat comorbid depression/psychosis
• Simplify regimen (once daily, fixed-dose combinations)
• Pill organizers, phone alarms, blister packs
• OAMT for IDU patients (structured dispensing improves adherence)
• Long-acting injectable ART (cabotegravir + rilpivirine monthly IM), emerging option

1.9 HIV TESTING AND COUNSELING

Voluntary Counseling and Testing (VCT)

Components of VCT:

1. Pre-test counseling: Risk assessment, meaning of test, implications of results, informed consent
2. HIV Testing: ELISA (4th generation, detects p24 antigen + anti-HIV antibody), confirmatory Western Blot or NAAT
3. Post-test counseling: Positive or negative results communicated with support, linkage to care

Window Period:

• 4th generation ELISA: ~18 days (detects p24 antigen early)
• 3rd generation ELISA: ~22 days
• NAAT: ~10 days
• Important: A negative test in window period does not exclude infection

PPTCT (Prevention of Parent-to-Child Transmission):

• Routine testing of all pregnant women
• ART for mother + infant prophylaxis
• Avoidance of breastfeeding (or ART-covered breastfeeding if formula unavailable)

Provider-Initiated Testing and Counseling (PITC):

• Opt-out testing in clinical settings (TB clinics, STI clinics, ANC)

1.10 HIV-RELATED STIGMA

Types of stigma:

1. Instrumental stigma: Fear of contagion
2. Symbolic stigma: Moral judgment (association with "immoral" behavior)
3. Courtesy stigma: Stigma extending to family members
4. Internalized stigma: Self-stigma, shame, worthlessness

Psychiatric impact:

• Delays HIV testing and disclosure
• Reduces ART adherence
• Increases depression and anxiety
• Reduces social support
• Associated with suicidality

UNAIDS 3 Zeros approach: Zero new infections, zero AIDS-related deaths, zero discrimination

PART 2: PARKINSON'S DISEASE & PSYCHIATRY

2.1 OVERVIEW

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. It is primarily characterized by dopaminergic neuronal loss in the substantia nigra pars compacta, producing the classic motor tetrad. However, PD is now understood as a whole-brain, whole-body disease with extensive non-motor manifestations, particularly neuropsychiatric.

Key neuropathology: Lewy bodies (eosinophilic intracytoplasmic inclusions composed primarily of alpha-synuclein aggregates)

Braak staging of PD pathology:

• Stages 1–2: Medulla, olfactory bulb (non-motor symptoms: anosmia, constipation, REM sleep disorder)
• Stages 3–4: Midbrain (substantia nigra, motor symptoms emerge)
• Stages 5–6: Cortex (cognitive, psychiatric symptoms)

2.2 DEPRESSION IN PARKINSON'S DISEASE

Prevalence: 40–50% (most common neuropsychiatric symptom of PD)

Point prevalence: 17% MDD, 22% minor depression/dysthymia

Key distinction: PD depression is not simply reactive, it has neurobiological underpinnings distinct from primary MDD

Neurobiological Basis

• Loss of noradrenergic neurons in the locus coeruleus (degeneration precedes substantia nigra)
• Loss of serotonergic neurons in the raphe nuclei
• Mesolimbic dopamine depletion (beyond nigrostriatal)
• Orbitofrontal cortex involvement

Clinical Features of PD Depression vs Primary MDD

Note: Depression is a prodromal feature of PD, may appear years before motor symptoms (Braak stages 1–2 involvement of serotonergic/noradrenergic systems)

Assessment

• HDRS (Hamilton Depression Rating Scale), most validated in PD
• MADRS, better for measuring change
• GDS-15 (Geriatric Depression Scale), useful, avoids somatic overlap
• BDI has somatic items that overlap with PD

Treatment

Pharmacological:

• SSRIs first-line: Paroxetine (most studied), escitalopram, sertraline; may slightly worsen motor symptoms (paroxetine has anticholinergic effects)
• SNRIs: Venlafaxine effective in controlled trials
• TCAs: Nortriptyline effective but anticholinergic side effects (confusion, urinary retention in elderly); desipramine also used
• Dopamine agonists: Pramipexole has antidepressant properties (beyond its motor effects)
• MAO-B inhibitors: Rasagiline, Selegiline, some antidepressant evidence; avoid combining with SSRIs (serotonin syndrome risk)
• ECT: Effective for severe PD depression; bonus: temporarily improves motor symptoms (PD motor symptoms respond to ECT)

Non-pharmacological:

• Cognitive Behavioral Therapy (CBT), adapted for PD
• Exercise (aerobic exercise has antidepressant and possible neuroprotective effects)
• Optimize dopaminergic therapy first (motor symptom control improves mood)
• Social support, peer support groups

2.3 ANXIETY IN PARKINSON'S DISEASE

Prevalence: 30–40%

Often comorbid with depression (anxiety-depression couplet very common in PD)

Types:

1. Generalized anxiety (most common)
2. Panic attacks, often coincide with "OFF" state (low dopamine fluctuations)
3. Social phobia, related to embarrassment about motor symptoms
4. Specific phobias, falling phobia

Key feature: "OFF-period anxiety", anxiety correlates with dopamine fluctuations. Patients experience intense anxiety, panic, dysphoria when dopaminergic medication wears off. This is not a primary psychiatric condition, it responds to optimization of dopamine therapy (smoother motor control).

Treatment:

• Optimize dopaminergic therapy (prevent OFF periods)
• SSRIs/SNRIs for anxiety
• Buspirone: Limited evidence
• Benzodiazepines: Use cautiously (falls risk, cognitive effects)
• CBT effective

2.4 PSYCHOSIS IN PARKINSON'S DISEASE

Prevalence: 20–40% over disease course; up to 75% in advanced disease

Clinical Features

Spectrum of psychotic symptoms:

1. Illusions, misidentifying objects/shadows (early)
2. Presence hallucinations, sensing someone behind them (early, benign)
3. Passage hallucinations, brief peripheral vision movement (early, benign)
4. Formed visual hallucinations (VH), most characteristic of PD psychosis
5. People, animals, objects
6. Usually non-threatening initially ("friendly visitors")
7. Clear consciousness (can distinguish from reality)
8. Eventually become frightening
9. Auditory hallucinations, less common; when prominent, consider DLB or comorbid psychiatric illness
10. Delusions, typically paranoid, persecutory, or Othello syndrome (morbid jealousy)

Risk Factors for PD Psychosis

• Advanced disease, older age
• Higher doses of dopaminergic medication
• Dementia (strongest predictor)
• Visual impairment
• Sleep disturbance
• Depression
• Polypharmacy (particularly anticholinergics, amantadine)

Pathophysiology

• Cortical Lewy body pathology
• Serotonergic dysfunction (5-HT2A)
• Dopaminergic overstimulation (iatrogenic, medication effect)
• Cholinergic dysfunction (ACh deficit in PD-dementia)
• REM sleep behavior disorder as precursor

Management: Step-Wise Approach

Step 1, Address reversible causes:

• Review medications: Reduce/discontinue in order: anticholinergics → amantadine → MAO-B inhibitors → dopamine agonists → COMT inhibitors → reduce levodopa (reluctantly)
• Treat concurrent infections (UTI common trigger in elderly)
• Correct metabolic derangements, optimize sleep

Step 2, Antipsychotic Treatment:

IMPORTANT NOTE ON PIMAVANSERIN (vs PIMELOZIDE):

• The drug approved in PD is pimavanserin (not pimelozide/pimeliazide, exam typo to watch for)
• Novel mechanism: selective 5-HT2A inverse agonist/antagonist
• No motor worsening; FDA-approved 2016

2.5 IMPULSE CONTROL DISORDERS (ICD) IN PARKINSON'S DISEASE

Prevalence: ~13.6% of PD patients on dopamine agonists (DOMINION study, Weintraub 2010)

Types

1. Pathological gambling, most common ICD
2. Hypersexuality, may cause significant marital distress
3. Compulsive eating/binge eating
4. Compulsive shopping (oniomania)
5. Punding, complex, stereotyped, repetitive behaviors (sorting, collecting, tinkering)
6. Dopamine Dysregulation Syndrome (DDS), see below

Risk Factors

• Dopamine agonists (pramipexole, ropinirole, rotigotine, non-ergot agonists)
• Younger age of onset
• Male sex
• History of impulsivity or substance use
• Family history of gambling

Mechanism

• Mesolimbic (reward) dopamine pathway overstimulation by dopamine agonists
• Dopamine agonists have relatively preferential affinity for D3 receptors (limbic/reward pathway) compared to levodopa
• The dorsal striatum (motor) may be adequately medicated while the ventral striatum (reward) is over-medicated

Management

• First step: Reduce or stop dopamine agonist
• May require accepting motor worsening or using DBS to allow agonist reduction
• CBT for gambling disorder
• Naltrexone (opioid antagonist), some evidence for ICD in PD
• SSRI for compulsive eating

2.6 DOPAMINE DYSREGULATION SYNDROME (DDS)

Definition: Compulsive use and misuse of dopaminergic medications in PD, beyond what is required for motor symptom control; characterized by addictive behavior toward levodopa/dopamine agonists

Features:

• Patient demands and takes excessive medication doses
• Hoards medications
• Mood fluctuations tied to medication, extreme dysphoria in OFF state, hypomanic/euphoric in ON state
• Aggression when medication withheld
• Hedonistic homeostatic dysregulation
• May have paranoia, psychosis in context of excessive dosing

Risk factors: Previous substance use disorder, impulsive personality, younger onset PD

Treatment:

• Very difficult, reducing medication causes severe motor OFF states
• Psychiatric support, family education
• Opioid antagonists (limited evidence)
• Consider DBS (reduces medication requirement, breaks the cycle)

2.7 COGNITIVE IMPAIRMENT AND DEMENTIA IN PD

Parkinson's Disease Dementia (PDD)

Prevalence: ~80% of PD patients will develop dementia over 20 years of disease

Onset: Usually >10 years after motor symptom onset (distinguishes from DLB, see below)

Cognitive profile:

• Frontosubcortical pattern
• Executive dysfunction (prominent, planning, working memory, set-shifting)
• Attention impairment
• Visuospatial deficits
• Memory: Retrieval > Encoding deficit (use cues → improves recall)
• Language: Relatively spared until late

Treatment:

• Rivastigmine (Exelon): Only FDA-approved agent for PDD (Emre et al., 2004, EXPRESS trial)
• Donepezil: Used off-label, evidence for efficacy
• Memantine: Some evidence for PDD
• Avoid: Anticholinergics (worsen cognition markedly)

DLB vs PDD: The "One-Year Rule"

Clinically, DLB and PDD are probably the same disease at different time points, together called "Lewy body spectrum disorders"

2.8 SLEEP DISORDERS IN PARKINSON'S DISEASE

Prevalence of sleep disturbance: >90% of PD patients

Types

1. REM Sleep Behavior Disorder (RBD):
2. Prodromal marker of PD (may precede motor symptoms by >10 years)
3. Acting out dreams during REM sleep (no atonia)
4. Punch, kick, shout during sleep
5. Risk of injury to self or bed partner
6. Treatment: Clonazepam (0.25–0.5 mg), melatonin (high dose, 3–12 mg)

1. Excessive Daytime Sleepiness (EDS):
2. Common; multifactorial
3. Dopamine agonists are major cause (especially pramipexole, "sleep attacks")
4. Sleep attacks: Sudden irresistible sleep (can occur while driving)
5. Treat: Reduce/change agonist; modafinil, caffeine

1. Insomnia:
2. Nocturia, pain, rigidity, depression, medication effects
3. Sleep fragmentation in PD common

1. Restless Legs Syndrome (RLS):
2. More common in PD
3. Responds to dopaminergic therapy

2.9 APATHY IN PARKINSON'S DISEASE

Definition: Quantitative reduction in motivation (goal-directed behavior) without primary mood disturbance

Prevalence: 40–70%

Often confused with depression but important distinctions:

• Apathy: Reduced motivation, no distress about it, no sadness
• Depression: Negative affect (sadness, guilt), distress present

Assessment: Starkstein Apathy Scale, Lille Apathy Rating Scale

Treatment:

• Optimize dopaminergic therapy (dopamine is the neurobiological substrate of motivation)
• Rivastigmine (cholinesterase inhibitor)
• Some evidence for methylphenidate
• Dopamine agonists: Can improve apathy

2.10 DEEP BRAIN STIMULATION (DBS) AND PSYCHIATRIC EFFECTS

DBS targets in PD:

• Subthalamic nucleus (STN), most common target; best for tremor, rigidity
• Globus pallidus internus (GPi), good for dyskinesia
• Vim thalamus, tremor only

Psychiatric Effects of DBS

Beneficial:

• Reduced depression in many patients (especially if related to motor fluctuations)
• May improve apathy somewhat

Adverse:

• Depression: Can worsen in some patients (paradoxically)
• Mania/Hypomania: Seen with STN DBS; stimulation of limbic STN territory
• Suicide: Increased suicide rate post-DBS (3x higher); mechanism unclear (mood changes, relationship changes, changed expectations)
• Impulse control disorders: May improve (medication reduction allows) or persist
• Cognitive decline: STN-DBS may cause minor executive and verbal fluency decline
• Personality changes: Reported, "I don't feel like myself" phenomenon
• Reduction in medication post-DBS allows reduction of dopamine agonists → may improve ICD

PART 3: HUNTINGTON'S DISEASE

3.1 GENETICS

• Gene: HTT gene on chromosome 4p16.3
• Mutation: CAG trinucleotide repeat expansion encoding polyglutamine in huntingtin protein
• Normal: ≤26 repeats
• Intermediate/Reduced penetrance: 27–35 repeats (not HD but may expand in offspring)
• Full penetrance: ≥40 repeats (all will develop HD)
• Mutable normal: 36–39 repeats (some may develop HD)

Anticipation: CAG repeats tend to expand with each generation; especially with paternal transmission

Juvenile HD: >60 repeats; onset <20 years; rigid (Westphal variant, akinetic-rigid, not choreic); often inherited from affected father

Inheritance

• Autosomal dominant, 50% risk to each child
• Fully penetrant when >40 repeats
• Both sexes equally affected

3.2 CLINICAL FEATURES

Motor Features

• Chorea: Involuntary, jerky, flowing movements (begin with subtle restlessness, fidgeting)
• Motor impersistence: Inability to sustain motor actions (darting tongue, "milkmaid grip")
• Gait: "Drunken sailor" gait, wide-based
• Dysarthria and dysphagia (progressive)
• Oculomotor abnormalities: Slow saccades (characteristic, diagnostic utility)
• Bradykinesia/rigidity: Develops later (or early in juvenile Westphal variant)

Cognitive Decline

• Subcortical dementia pattern (similar to PD, executive dysfunction, memory retrieval, slowed processing)
• Striatal and frontal circuit degeneration
• Not primarily amnestic (unlike Alzheimer's)
• Cognitive decline often precedes motor symptoms

3.3 PSYCHIATRIC FEATURES: HIGH YIELD

Psychiatric symptoms may PRECEDE motor symptoms by years, often the initial presentation to psychiatry

Depression

• Prevalence: 30–40%
• Often the first symptom
• Increased suicide risk: HD patients have ~4x higher suicide rate than general population
• Two high-risk periods: Just after diagnosis and early motor symptoms (loss of independence)
• Treatment: SSRIs first-line; TCAs avoided (anticholinergic effects worsen cognitive symptoms)

Irritability and Aggression

• Most common psychiatric symptom across all stages (some studies)
• Explosive, unpredictable
• Directly related to striatal degeneration (loss of inhibitory control)
• Treatment: SSRIs (especially fluoxetine, sertraline), valproate, atypical antipsychotics

Apathy

• Common and often underrecognized
• Distinct from depression (see PD section)
• Worsens caregiving burden

Obsessive-Compulsive Symptoms

• Repetitive, perseverative behaviors
• Rigidity of thought
• Not always ego-dystonic (may not have full OCD phenomenology)
• Driven by frontostriatal circuit dysfunction

Psychosis

• Less common (~10%)
• Paranoid delusions, persecutory
• Hallucinations (auditory, visual)
• Treatment: Atypical antipsychotics (tetrabenazine caution, can cause depression/akathisia)

Mania/Hypomania

• Uncommon (~5%)
• Usually brief, episodic
• May occur before diagnosis

Sexual Disinhibition

• Particularly seen in advanced disease
• May be manifestation of frontal disinhibition

3.4 MANAGEMENT OF HD

Motor

• Tetrabenazine (TBZ): FDA-approved for HD chorea; VMAT2 inhibitor (depletes dopamine); CAUSES depression, monitor carefully
• Deutetrabenazine: New VMAT2 inhibitor, longer half-life, fewer side effects than TBZ; also FDA-approved
• Valbenazine: VMAT2 inhibitor primarily used for tardive dyskinesia, also has HD utility
• Antipsychotics (haloperidol, olanzapine): Reduce chorea via D2 blockade

Psychiatric

• Depression: SSRIs, ECT for severe
• Irritability: SSRIs, valproate, antipsychotics
• Psychosis: Atypical antipsychotics
• Apathy: No proven treatment; stimulants tried
• Sleep: Mirtazapine, clonazepam

No Disease-Modifying Treatment Exists

Huntingtin-lowering strategies in trials:

• Antisense oligonucleotides (ASO)
• RNA interference (RNAi)
• Gene editing (CRISPR-Cas9), future

3.5 GENETIC COUNSELING IN HD: ETHICAL ISSUES

Key ethical principles:

1. Autonomy: Right to know vs right not to know
2. Beneficence/Non-maleficence: Genetic testing can cause severe psychological distress
3. Justice: Insurance discrimination implications
4. Confidentiality: Family members at risk, duty to warn vs patient privacy conflict

Predictive Testing Protocol (HDSA guidelines):

1. Pre-test counseling (minimum 2 sessions) by genetics counselor and psychiatrist
2. Psychological assessment, exclude active suicidality, acute psychiatric illness
3. Adequate support system confirmed
4. Informed consent
5. Support during and after test disclosure
6. Long-term follow-up

Children: Testing asymptomatic children generally not recommended (no medical benefit in childhood; right not to know; cannot give informed consent)

Prenatal testing: Available, preimplantation genetic diagnosis (PGD) allows selection of unaffected embryos without revealing parental status

Psychological impact of positive result:

• Acute grief response
• Depression, suicidality (greatest risk in first 6 months post-result)
• Some experience "survivor guilt" if sibling tests negative
• Some paradoxically feel relief (end of uncertainty)

PART 4: MULTIPLE SCLEROSIS & PSYCHIATRY

4.1 OVERVIEW

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the CNS.

• Prevalence: 2.5 million worldwide; rare in India but increasing
• Demographics: More common in women (F:M = 2–3:1); onset typically 20–40 years
• Pathology: Inflammatory demyelinating plaques in white matter (periventricular, juxtacortical, infratentorial, spinal cord)
• Course types: RRMS (relapsing-remitting, 85%), SPMS (secondary progressive), PPMS (primary progressive), PRMS

4.2 DEPRESSION IN MS

Prevalence: 50% lifetime risk, highest of any neurological illness (compared by prevalence)

Why so high?

1. Direct demyelination of limbic and frontal tracts
2. Systemic immune dysregulation (pro-inflammatory cytokines → depressogenic)
3. Interferon-beta (IFN-β), disease-modifying therapy, causes depression in 20–30% (via IDO pathway, tryptophan depletion, cytokine-mediated)
4. Psychosocial burden: unpredictable course, disability, uncertainty, loss
5. Steroid-associated mood disturbance (used for relapses)

Clinical note: Interferon-induced depression is clinically important, monitor mood at each visit; switch to glatiramer acetate or natalizumab if depressive; SSRIs can be used prophylactically in vulnerable patients

Treatment:

• SSRIs first-line (sertraline most studied in MS)
• Cognitive therapy evidence-based
• Exercise (aerobic) has evidence in MS depression
• Switch IFN-β if implicated

4.3 PSEUDOBULBAR AFFECT (PBA)

Also called: Pathological laughing and crying, emotional lability, involuntary emotional expression disorder (IEED)

Prevalence in MS: 10%

Definition: Episodes of sudden, involuntary laughing or crying that are disproportionate to or inconsistent with the underlying emotional state

Key features:

• No voluntary control
• Episodes may not match inner feelings (patient may cry without feeling sad, or laugh without feeling happy)
• Episodes triggered by minor stimuli
• Patients feel embarrassed, socially withdrawn

Distinguish from:

• Emotional lability in mania/BPD: Full emotional experience matches the expression (patient feels what they show)
• Depression with tearfulness: Congruent emotion, patient feels sad

Mechanism: Disruption of corticobulbar tracts (prefrontal → brainstem/cerebellum circuits) → loss of voluntary suppression of emotional expression

Treatment:

• Dextromethorphan/Quinidine (Nuedexta): FDA-approved for PBA; effective
• SSRIs: Effective (citalopram, fluoxetine, often dramatic response)
• TCAs: Effective; amitriptyline used historically
• Response is rapid (days), unlike depression

4.4 COGNITIVE IMPAIRMENT IN MS

Prevalence: 40–65% of MS patients

Pattern: Primarily affects:

• Processing speed (most sensitive measure, Symbol Digit Modalities Test)
• Episodic memory (learning efficiency)
• Working memory
• Complex attention

Pattern is NOT Alzheimer's-like, language and simple attention relatively spared until late

Assessment tool: BICAMS (Brief International Cognitive Assessment for MS), 3 tests; SDMT, CVLT, BVMTR

Relationship to lesion load: Correlates with total lesion volume and brain atrophy (gray matter atrophy more predictive than white matter lesions)

4.5 EUPHORIA SCLEROTICA: MYTH vs REALITY

Historical concept: "Euphoria sclerotica", notion that MS patients experience inappropriate cheerfulness/euphoria

Current understanding:

• True pathological euphoria (inappropriate/sustained cheerfulness inconsistent with circumstances) is RARE (<5%)
• Most reported "euphoria" in historical studies was actually:
• Cognitive impairment (reduced insight into disability)
• Pseudobulbar laughing (misinterpreted as euphoria)
• Selection bias in older studies (happier patients more visible)
• Exam point: The current view is that euphoria sclerotica is largely a myth, DEPRESSION is the dominant mood disturbance in MS

PART 5: SLE & NEUROPSYCHIATRY

5.1 NEUROPSYCHIATRIC SLE (NPSLE)

Prevalence: 25–75% of SLE patients (depending on case definition)

ACR classification (1999): 19 specific NPSLE syndromes identified

5.1.1 NPSLE Syndromes: Classification

CNS Manifestations:

• Aseptic meningitis
• Cerebrovascular disease
• Demyelinating syndrome
• Headache (not attributable to other cause)
• Movement disorder (chorea)
• Myelopathy
• Seizures
• Acute confusional state (ACS)
• Anxiety disorder
• Cognitive dysfunction
• Mood disorder
• Psychosis

PNS Manifestations:

• Guillain-Barre syndrome
• Autonomic disorder
• Mononeuropathy
• Myasthenia gravis
• Cranial neuropathy
• Plexopathy
• Polyneuropathy

5.1.2 Psychiatric Manifestations of NPSLE

Psychosis:

• Prevalence: 2–8% of SLE patients
• Acute confusional state + psychotic features
• Can be first manifestation of SLE
• Differential: Steroid-induced psychosis vs SLE psychosis
• SLE psychosis: Elevated anti-dsDNA, low complement, NPSLE on imaging
• Steroid psychosis: Dose-dependent, within days of starting/increasing steroids, positive with dose reduction
• Treatment: Immunosuppression (if SLE cause) + antipsychotics

Depression:

• Most common psychiatric NPSLE manifestation
• Mechanism: Cytokines, anti-neuronal antibodies, direct cerebrovascular disease, HPA dysregulation
• Also consider: Corticosteroid-induced depression (dose-dependent)
• SSRIs effective

Cognitive Impairment:

• ~80% on formal testing
• Pattern: Attention, processing speed, memory
• "Lupus fog", subjective cognitive complaints very common
• Correlates with antiphospholipid antibodies

5.1.3 Antiphospholipid Syndrome (APS) in SLE

Prevalence: ~30% of SLE patients have antiphospholipid antibodies

Clinical: Thrombosis (arterial and venous), obstetric complications, thrombocytopenia

Neuropsychiatric implications:

• Stroke/TIA → focal neurological deficits, vascular dementia
• Cerebral venous thrombosis → headache, papilledema, seizures
• Cognitive impairment (chronic small vessel disease)
• Sneddon syndrome: Livedo reticularis + stroke (APS-related)
• Psychiatric manifestations: Depression, psychosis (mechanism unclear, may be direct effect of antiphospholipid antibodies on neuronal function)
• Treatment: Anticoagulation (warfarin), hydroxychloroquine

5.1.4 Steroid-Induced Psychiatric Effects

Steroids are commonly used in SLE, MS relapses, and other neurological conditions:

Dose thresholds:

• Psychosis: Usually >40 mg/day prednisone equivalent
• Mania/euphoria: Higher doses (>80 mg/day)

Management:

• Reduce dose if possible
• Antipsychotics for psychosis/mania (short-term)
• Lithium prophylaxis if patient requires repeated high-dose steroids and has history of steroid-induced mania
• Do NOT use sodium restriction (can cause mood problems through steroid-sodium interaction, less relevant with modern agents)

PART 6: AUTOIMMUNE ENCEPHALITIS

6.1 ANTI-NMDA RECEPTOR ENCEPHALITIS

Discovery: Dalmau et al., 2007, described in young women with ovarian teratomas and encephalitis

Epidemiology:

• Most common autoimmune encephalitis
• Young women (especially 12–45 years) predominantly affected
• Ovarian teratoma in 50–60% of female cases (teratoma contains neural tissue that becomes antigenic)
• Can occur without teratoma (especially in children, males)

Clinical Phases

Phase 1 (Prodromal, first 2–5 days):

• Viral prodrome: fever, headache, malaise
• Often misdiagnosed as viral encephalitis

Phase 2 (Psychiatric, first 2 weeks):

• PSYCHIATRIC SYMPTOMS DOMINATE
• Agitation, anxiety, bizarre behavior
• Psychosis: Hallucinations (auditory, visual, tactile), delusions
• Emotional lability
• The psychiatric phase is the most likely presentation to psychiatry, often admitted to psychiatric wards first

Phase 3 (Neurological, weeks 2–4):

• Seizures (usually early)
• Movement disorders: Orofacial dyskinesias (repetitive mouth movements, tongue thrusting), choreoathetosis, abnormal postures, very characteristic
• Autonomic instability: Tachycardia, hyperthermia, hypertension, diaphoresis
• Decreased consciousness
• Hypoventilation (may require ventilation)

Phase 4 (Recovery, weeks to months):

• Gradual improvement with treatment
• Relapsing course possible

Investigations

• CSF: Lymphocytic pleocytosis (60%), elevated protein, normal glucose
• EEG: Diffuse slowing, "extreme delta brush" pattern (highly specific, 30% of cases)
• MRI brain: Often normal; may show T2/FLAIR hyperintensity in limbic structures
• Key test: Anti-NMDAR IgG antibodies in CSF (more sensitive than serum)
• Ovarian ultrasound/CT: Mandatory in all women of childbearing age

Pathophysiology

Anti-NMDAR antibodies (IgG targeting GluN1 subunit):

• Reduce NMDAR surface expression and synaptic localization
• Disinhibit dopamine pathways (NMDARs normally inhibit dopamine release → antibody-mediated reduction → dopamine excess → psychosis)
• Glutamate hypothesis of schizophrenia (NMDAR hypofunction) is essentially the mechanism here

Treatment

First-line immunotherapy:

1. High-dose IV methylprednisolone (1g/day × 5 days)
2. IVIG (2g/kg over 5 days)
3. Plasmapheresis (plasma exchange)

Second-line (if no response at 2–4 weeks):

1. Rituximab (anti-CD20 monoclonal antibody, B cell depletion)
2. Cyclophosphamide

Tumor removal:

• Teratoma removal is mandatory and speeds recovery, often dramatic improvement post-oophorectomy

Supportive:

• Antiepileptics for seizures
• Antipsychotics for behavioral symptoms (low dose, carefully)
• ICU support if ventilated

Prognosis:

• With treatment: >80% substantial improvement
• 20–25% relapse (higher without tumor removal or second-line therapy)
• Most recover fully but some have residual cognitive deficits

Anti-NMDAR Encephalitis vs Schizophrenia: Distinguishing Features

6.2 LGI1 (LEUCINE-RICH GLIOMA-INACTIVATED 1) ENCEPHALITIS

Demographics: Older men (60s–70s), unlike anti-NMDAR

Association: VGKC antibody complex (the LGI1 antibody was previously called "anti-VGKC")

No tumor association (unlike anti-NMDAR, teratoma)

Clinical Features:

• Faciobrachial dystonic seizures (FBDS): Highly characteristic, brief (<3 seconds), frequent (up to 100/day) facial + ipsilateral arm dystonic movements
• Limbic encephalitis: Memory impairment, confusion, psychiatric symptoms
• SIADH (hyponatremia), very common; helps differentiate from other encephalitides
• Amnesia (often severe and early)
• Psychiatric: Anxiety, depression, psychosis

Investigations:

• LGI1 antibodies in serum and CSF
• MRI: T2/FLAIR hyperintensity in medial temporal lobes, basal ganglia
• EEG: Temporal epileptiform activity

Treatment:

• Same first-line immunotherapy as anti-NMDAR
• Responds well to steroids
• Antiepileptics often ineffective for FBDS (seizures are immunotherapy-responsive)

6.3 OTHER AUTOIMMUNE ENCEPHALITIDES

PART 7: NEUROSYPHILIS

7.1 OVERVIEW

Treponema pallidum invades the CNS early in infection (within weeks), but most cases are cleared by immune response. Neurosyphilis develops when CNS invasion is not cleared.

Risk factors for neurosyphilis: HIV co-infection (dramatically increases risk, 7–10x), untreated/inadequately treated syphilis, immunosuppression

7.2 CLASSIFICATION OF NEUROSYPHILIS

7.2.1 Asymptomatic Neurosyphilis

• CSF abnormalities (elevated cells, protein, positive VDRL) without symptoms
• Identified only by lumbar puncture

7.2.2 Acute Syphilitic Meningitis

• Within 2 years of primary infection
• Acute meningitis: Headache, meningismus, CN palsies (II, III, IV, VII, VIII)
• Usually resolves spontaneously but may progress

7.2.3 Meningovascular Syphilis

• 5–12 years after primary infection
• Endarteritis of cerebral vessels → ischemic strokes
• Younger patient + stroke + high-risk behavior → consider syphilis
• Hubner's endarteritis: Inflammation of vasa vasorum + adventitia of large vessels
• Clinical: Prodrome of headache, dizziness, personality change → focal stroke

7.2.4 General Paresis of the Insane (GPI)

Onset: 15–20 years after primary infection

Pathology: Diffuse cortical involvement (meningoencephalitis with parenchymal damage)

Mnemonic: "PARESIS"

• Personality change
• Affect (lability, depression, mania)
• Reflexes (hyperreflexia, Argyll Robertson pupil)
• Eye (Argyll Robertson pupil, see below)
• Sensory changes
• Intellect decline (dementia)
• Speech (dysarthria)

Psychiatric features (GPI):

• Grandiose delusions ("I am God, I am Napoleon"), classic but actually uncommon
• Depression more common
• Personality change, irritability
• Progressive dementia
• Mania with grandiosity

7.2.5 Tabes Dorsalis

Onset: 15–25 years after primary infection

Pathology: Degeneration of posterior columns and dorsal nerve roots

Clinical features:

• Lightning pains (stabbing, lancinating pains in legs)
• Sensory ataxia (positive Romberg)
• Loss of deep tendon reflexes
• Loss of vibration/proprioception
• Charcot joints (neuropathic arthropathy)
• Argyll Robertson pupil
• Bladder dysfunction (retention → overflow)

7.2.6 Argyll Robertson Pupil: High Yield

Contrast with Holmes-Adie pupil:

• Large, dilated pupil
• Slow tonic response to light
• Absent knee/ankle jerks
• Benign condition

7.2.7 Diagnosis and Treatment

CSF in Neurosyphilis:

• VDRL (CSF), most specific test (high specificity, low sensitivity, ~70%)
• FTA-ABS (serum), screening
• TPHA/TPPA, confirmatory
• WBC >5/μL and protein elevation
• Reactive CSF VDRL = definitive neurosyphilis (when clinical suspicion present)

Treatment:

• Aqueous crystalline benzyl penicillin G 18–24 million units/day IV × 10–14 days
• Alternative: Procaine penicillin IM + probenecid × 10–14 days
• Penicillin allergy: Desensitize if possible; alternatives (ceftriaxone, doxycycline) less evidence
• Jarisch-Herxheimer reaction: Fever, chills, hypotension 2–8 hours after first dose of penicillin; pre-treat with paracetamol

PART 8: PRION DISEASES

8.1 OVERVIEW

Prion diseases (Transmissible Spongiform Encephalopathies, TSEs) are rare, fatal neurodegenerative diseases caused by misfolded prion proteins (PrP^Sc) that convert normal cellular prion protein (PrP^C) to an abnormal form.

Key principle: No DNA or RNA, purely protein-mediated transmission

Spongiform change, vacuolation of neuropil (Swiss cheese appearance)

8.2 CREUTZFELDT-JAKOB DISEASE (CJD)

Sporadic CJD (sCJD): 85%

Epidemiology: 1–2 per million/year; median age onset 65 years

Course: Rapidly progressive dementia; death usually within 4–6 months (median 4 months)

Clinical features:

• Rapidly progressive dementia, cognitive decline over weeks
• Cerebellar ataxia
• Visual disturbances (cortical blindness, visual hallucinations)
• Myoclonus, stimulus-sensitive; episodic jerks
• Pyramidal/extrapyramidal signs
• Akinetic mutism (late stage)

Investigations:

Familial CJD (fCJD): 10–15%

• PRNP gene mutations
• Autosomal dominant
• Includes Gerstmann-Straussler-Scheinker (GSS) and Fatal Familial Insomnia (FFI)

Variant CJD (vCJD): Rare

• Caused by BSE (bovine spongiform encephalopathy), "mad cow disease" transmission to humans via infected beef
• Younger patients (mean age 29 years)
• Longer course (~13 months)
• Psychiatric features prominent early: Depression, anxiety, withdrawal, sensory symptoms
• Neurological features later: Ataxia, involuntary movements, dementia
• Pulvinar sign on MRI (T2 hyperintensity in posterior thalamus), highly suggestive
• Tonsillar biopsy: Shows PrP^Sc (not brain biopsy required), can be diagnostic ante-mortem

Iatrogenic CJD

• Transmission via contaminated surgical instruments, dura mater grafts, growth hormone (cadaveric), corneal transplants
• Incubation months to decades

8.3 KURU

• Fore people of Papua New Guinea
• Transmitted by ritual cannibalism (consumption of human brain tissue)
• Cerebellar ataxia dominant feature ("laughing disease")
• Virtually eliminated with cessation of cannibalism
• Shivering tremors → ataxia → dementia
• Historical significance: Led Gajdusek to the prion hypothesis (Nobel Prize 1976)

8.4 FATAL FAMILIAL INSOMNIA (FFI)

• Mutation: D178N in PRNP (with Met at codon 129)
• Autosomal dominant
• Pathology: Selective degeneration of thalamus (anterior and mediodorsal nuclei)

Clinical stages:

1. Intractable insomnia + sympathetic hyperactivation (tachycardia, hyperhidrosis, hyperthermia, hypertension)
2. Hallucinatory stupor (acted-out dreams)
3. Complete insomnia + cognitive decline
4. Unresponsive coma → death

Duration: 7–25 months

PART 9: NEUROPSYCHIATRIC MANIFESTATIONS OF SYSTEMIC ILLNESS

9.1 RENAL FAILURE (UREMIC ENCEPHALOPATHY)

Mechanism: Accumulation of uremic toxins (guanidine compounds, indoles, phenols), disruption of neurotransmitter systems, fluid/electrolyte disturbances, hypertension

Clinical stages:

• Mild uremia: Fatigue, difficulty concentrating, personality change, insomnia
• Moderate uremia: Cognitive decline, confusion, restlessness, "restless legs," myoclonus
• Severe uremia: Delirium, seizures, stupor, coma
• Uremic asterixis, bilateral flapping tremor of outstretched hands

Dialysis-related psychiatric conditions:

1. Dialysis Dementia: Now rare; caused by aluminium accumulation in dialysate; progressive aphasia → dementia → seizures → death
2. Dialysis Disequilibrium Syndrome: Occurs during/after dialysis; cerebral edema from rapid osmotic changes; headache, nausea, delirium, seizures
3. Depression: Very common in dialysis patients (>25%)
4. Anxiety and PTSD (related to dependence on machine, mortality awareness)

Psychotropics in renal failure:

• Avoid: Lithium (renally cleared, accumulates; nephrotoxic, avoid in CKD)
• Avoid: Gabapentin/Pregabalin (renally cleared, dose reduce or avoid)
• Careful with: Risperidone, amisulpride (renally cleared)
• Generally safe: Olanzapine, quetiapine, lorazepam (hepatic metabolism)

9.2 HEPATIC FAILURE (HEPATIC ENCEPHALOPATHY)

Mechanism: Ammonia + other toxic metabolites (GABA agonists, false neurotransmitters, inflammatory cytokines) crossing BBB → neuroinflammation + altered neurotransmission

West Haven Criteria (grading):

Treatment: Lactulose, rifaximin, treat underlying cause, TIPS (transjugular intrahepatic portosystemic shunt) for refractory

Psychotropics in liver failure:

• Avoid: Valproate (hepatotoxic, increases ammonia)
• Avoid: Chlorpromazine, TCAs (sedating, lower seizure threshold)
• Careful with: Benzodiazepines (hepatic metabolism, accumulation; but lorazepam relatively safer in cirrhosis due to glucuronidation only)
• Safe: Low-dose haloperidol, quetiapine, oxazepam, temazepam (glucuronidation)

9.3 RESPIRATORY FAILURE (HYPOXIC AND HYPERCAPNIC ENCEPHALOPATHY)

Hypoxic Encephalopathy

• Acute: Anxiety, agitation, confusion → seizures → coma
• Chronic hypoxia (e.g., COPD): Personality change, cognitive decline, mood disturbance
• Post-resuscitation: Persistent vegetative state, cognitive sequelae

Hypercapnic Encephalopathy (CO2 Narcosis)

• Seen in COPD with respiratory failure
• Elevated CO2 → CNS acidosis → depression, confusion, drowsiness
• Classic: Warm extremities, bounding pulse, headache, asterixis, papilledema
• Treatment: Controlled oxygen therapy, NIV/ventilation

Sleep-Disordered Breathing (OSA) and Psychiatry

• OSA strongly associated with:
• Depression (30% of OSA patients)
• Cognitive impairment (attention, memory, executive function)
• Impulsivity and irritability
• Treatment-resistant depression (CPAP improves mood)
• Psychotic features (sleep deprivation effects)

9.4 THYROID AND PSYCHIATRIC CONDITIONS (Brief: Main Topic in NB-07)

9.5 WERNICKE'S ENCEPHALOPATHY AND KORSAKOFF'S SYNDROME (Neuropsychiatric intersection)

Etiology: Thiamine (B1) deficiency

High-risk groups: Chronic alcohol use disorder, malnutrition, prolonged vomiting (hyperemesis, chemotherapy), bariatric surgery

Wernicke's Encephalopathy (Acute)

Classic Triad:

1. Confusion/delirium (80%, most common)
2. Oculomotor abnormalities (nystagmus, lateral gaze palsy, complete ophthalmoplegia), 25%
3. Ataxia (gait ataxia), 23%

Full triad only in 16%, treat empirically with thiamine in any at-risk patient

Pathology: Bilateral petechial hemorrhages in:

• Mammillary bodies (classic)
• Periaqueductal gray
• Medial thalamus
• Hypothalamus
• Floor of fourth ventricle

Treatment: IV thiamine BEFORE glucose (glucose administration can precipitate acute WE in thiamine-deficient patients)

Korsakoff's Syndrome (Chronic)

Features:

1. Severe anterograde amnesia (cannot form new memories)
2. Retrograde amnesia (gap increases toward present, with temporal gradient)
3. Confabulation, unintentional (not deliberate lying), fills memory gaps with fabricated content
4. Relatively preserved immediate memory and remote memory
5. Anosognosia, lack of awareness of memory deficits

Prognosis: 20–25% recovery with treatment, 50% partial improvement, 25% permanent (irreversible)

Treatment: High-dose thiamine replacement; address alcohol dependence

9.6 ANTI-NMDAR ENCEPHALITIS: PSYCHIATRIC MIMICRY (Recap)

The most important message for psychiatric exams regarding autoimmune encephalitis:

Clinical pearls:

1. Any young woman with rapid-onset psychiatric symptoms + seizures + movement disorder = anti-NMDAR encephalitis until proven otherwise
2. These patients appear psychiatric at first, admitted to psychiatry wards, given antipsychotics, often not investigated adequately
3. CSF analysis and anti-NMDAR antibodies must be checked before diagnosing a "first psychotic episode" in atypical presentations
4. Red flags for organic psychosis: Fever, seizures, movement disorders, autonomic instability, decreased consciousness, rapid cognitive decline, age/sex atypicalities

9.7 WILSON'S DISEASE: NEUROPSYCHIATRIC MANIFESTATIONS

Genetics: ATP7B gene mutation (copper transporter); autosomal recessive; chromosome 13

Pathophysiology: Copper accumulates in liver, brain (lenticular nucleus), cornea (Kayser-Fleischer rings)

Neuropsychiatric features (50% of Wilson's present with neuropsychiatric symptoms):

• Personality change (disinhibition, impulsivity), often first symptom
• Depression (common; can precede neurological symptoms)
• Psychosis (rare but can resemble schizophrenia)
• Cognitive decline
• Anxiety, OCD-like symptoms

Neurological features:

• Dysarthria (often first neurological symptom)
• Tremor (wing-beating/rubral tremor characteristic)
• Ataxia, dystonia, parkinsonism
• Seizures (rare)

Kayser-Fleischer rings: Golden-brown deposits at Descemet's membrane of cornea; slit-lamp examination; present in >99% neurological Wilson's

Diagnosis:

• Serum ceruloplasmin: LOW
• 24-hour urinary copper: HIGH
• Liver biopsy: Copper quantification (gold standard)
• Slit-lamp: KF rings

Treatment:

• D-penicillamine (chelation), first-line
• Trientine (chelation, less side effects)
• Zinc (blocks intestinal copper absorption), maintenance
• Liver transplant: Curative for hepatic disease; improves neurological disease

SUMMARY TABLE: NEUROPSYCHIATRIC SYNDROMES BY PATHOLOGY TYPE

Model Answers

HIV, Parkinson's Disease & Other Neuropsychiatry

MODEL ANSWER 01

Q: Describe HIV-Associated Neurocognitive Disorders (HAND). Discuss the staging, pathophysiology, assessment, and management. (10 marks)

Introduction

HIV-Associated Neurocognitive Disorders (HAND) is an umbrella term for a spectrum of neurocognitive impairment that occurs directly as a consequence of HIV infection of the central nervous system. It was formally classified by Antinori et al. in 2007. With the advent of combination antiretroviral therapy (cART), the prevalence of severe HIV-Associated Dementia (HAD) has declined from 25–30% to approximately 2–8%, while milder forms (ANI, MND) now predominate.

1. Classification and Staging (3 marks)

The three-tier HAND classification (Antinori 2007):

Swipe to compare →

Six cognitive domains are assessed: learning/memory, attention/working memory, executive function, speed of information processing, language, and motor skills. Psychomotor slowing is the hallmark.

HAND is a subcortical dementia, retrieval deficits (not encoding failure), personality change, slowed processing. Contrast with Alzheimer's (cortical, aphasia, apraxia, agnosia).

2. Pathophysiology (3 marks)

HIV does not directly infect neurons (neurons lack CD4 receptors). Neurotoxicity occurs through:

a) Viral protein neurotoxicity:

• gp120: Binds CXCR4/CCR5 on neurons → calcium influx → excitotoxicity → apoptosis
• Tat protein: Disrupts blood-brain barrier, induces oxidative stress, dysregulates dopaminergic pathways
• Vpr: Promotes neuronal apoptosis

b) Macrophage/microglia-mediated injury:

• HIV infects macrophages and microglia → viral reservoir in CNS
• Activated microglia release: cytokines (TNF-α, IL-1β), quinolinic acid (NMDA agonist → excitotoxicity), reactive oxygen species
• Bystander neurotoxicity is the primary mechanism

c) Persistent immune activation:

• Even on ART, chronic microglial activation continues
• Blood-brain barrier disruption allows systemic inflammatory mediators to enter CNS
• "Inflammaging" contributes to progression

3. Assessment, IHDS (2 marks)

The International HIV Dementia Scale (IHDS) is the standard bedside tool:

Cutoff: ≤10 suggests HAD (sensitivity 74%, specificity 54%).

For milder forms (ANI/MND), formal neuropsychological battery is required. Screening tools: MoCA, HDS.

4. Management (2 marks)

a) ART optimisation:

• First and most important intervention
• Target CPE (CNS Penetration Effectiveness) score ≥8
• Drugs with high CNS penetration: Zidovudine (AZT), Nevirapine, Lopinavir/ritonavir

b) Symptomatic management:

• Depression (30–60% comorbidity): SSRIs (escitalopram, sertraline), first-line
• Psychosis: Atypical antipsychotics (HIV patients are very sensitive to EPS, avoid typicals)
• Sleep: Melatonin, low-dose quetiapine
• Cognitive rehabilitation: structured programmes

c) Treating OI:

• Any active CNS OI must be treated aggressively as it worsens HAND

d) Psychosocial:

• Address stigma, depression, adherence simultaneously

MODEL ANSWER 02

Q: A 32-year-old woman is admitted to a psychiatric ward with acute onset of auditory hallucinations, agitation, and bizarre behaviour over 10 days. She has no prior psychiatric history. Discuss the differential diagnosis and management, with special emphasis on autoimmune encephalitis. (10 marks)

Introduction

Acute-onset psychiatric symptoms in a young woman without prior psychiatric history must be evaluated systematically for organic aetiology before diagnosing primary psychotic illness. Anti-NMDA receptor encephalitis is the most common autoimmune encephalitis and characteristically presents to psychiatry first.

1. Differential Diagnosis (3 marks)

Red flags for organic cause:

• Acute/rapid onset (days, not months)
• Fever, preceding prodrome
• Seizures, particularly early
• Movement disorders (orofacial dyskinesias)
• Autonomic instability
• Altered/fluctuating consciousness
• Normal premorbid function
• Young female (ovarian teratoma association)

2. Anti-NMDAR Encephalitis, Clinical Profile (3 marks)

Anti-NMDAR encephalitis (Dalmau et al., 2007) is caused by IgG antibodies against the GluN1 subunit of the NMDA receptor.

Clinical phases:

Phase 1 (Prodromal, days 1–5): Viral prodrome, fever, headache

Phase 2 (Psychiatric, weeks 1–2):

• Agitation, psychosis (auditory/visual hallucinations, delusions)
• Emotional lability, bizarre behaviour
• This phase presents to psychiatry

Phase 3 (Neurological, weeks 2–4):

• Seizures (often early, can persist)
• Orofacial dyskinesias, choreoathetosis (characteristic)
• Autonomic instability (tachycardia, hyperthermia, blood pressure fluctuations)
• Decreased consciousness, hypoventilation

Phase 4 (Recovery): Gradual improvement over months

Epidemiology: Young women; ovarian teratoma in 50–60% of female cases; can occur without teratoma (children, males)

3. Investigations (2 marks)

4. Management (2 marks)

A. Immediate:

• ICU if autonomic instability or hypoventilation
• Low-dose antipsychotics for behaviour (minimal; monitor QTc)
• Antiepileptics for seizures

B. First-line immunotherapy (simultaneously):

• IV methylprednisolone 1g/day × 5 days
• IVIG 2g/kg over 5 days
• Plasmapheresis (especially if no response)

C. Second-line (if no response at 2–4 weeks):

• Rituximab (anti-CD20, B-cell depletion)
• Cyclophosphamide

D. Tumour removal:

• Ovarian teratectomy is mandatory, dramatically speeds recovery
• Most important single intervention for long-term outcome

Prognosis: >80% substantial recovery with treatment; 20–25% relapse.

MODEL ANSWER 03

Q: Discuss the psychiatric manifestations of Huntington's disease. Describe genetic counselling and ethical issues in predictive testing. (10 marks)

Introduction

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion (≥40 repeats) in the HTT gene on chromosome 4p16.3. Psychiatric symptoms are often the earliest and most distressing manifestations, they may precede motor symptoms by years and significantly contribute to the disease burden.

1. Psychiatric Manifestations (5 marks)

a) Depression (30–40%):

• Often the first presenting symptom
• Can precede motor symptoms by years
• Suicide risk is 4–7 times higher than general population
• Two high-risk periods: soon after diagnosis and onset of early motor disability
• Treatment: SSRIs (avoid TCAs, anticholinergic burden worsens cognition)

b) Irritability and Aggression (most common across all stages):

• Explosive, disproportionate outbursts
• Directly related to striatal degeneration and frontal disinhibition
• Often the feature that most distresses caregivers
• Treatment: SSRIs (fluoxetine, sertraline), valproate, low-dose atypical antipsychotics

c) Apathy (40–70%):

• Distinct from depression, no subjective distress, no negative affect
• Quantitative reduction in motivation
• Worsens progressively
• Often mistaken for depression, important distinction for treatment

d) Obsessive-Compulsive Symptoms:

• Perseverative, rigid behaviours
• Driven by frontostriatal circuit dysfunction
• Not always ego-dystonic
• SSRIs with augmentation if needed

e) Psychosis (~10%):

• Paranoid delusions, hallucinations
• Usually in mid-stage disease
• Treatment: Atypical antipsychotics (caution, tetrabenazine already used for chorea and causes depression/akathisia)

f) Cognitive Decline:

• Subcortical dementia pattern (executive dysfunction, slowed processing, retrieval memory deficits)
• Progresses invariably
• No approved treatment

g) Sleep Disturbance:

• Insomnia, circadian rhythm disruption, REM sleep abnormalities
• Mirtazapine, clonazepam useful

2. Genetic Counselling and Ethical Issues (5 marks)

A. Predictive Testing Protocol (HDSA/EHD Guidelines):

Predictive testing for HD is ethically complex because:

• There is no disease-modifying treatment
• A positive result has profound psychological consequences
• Family members are simultaneously affected

Standard protocol (minimum):

1. Pre-test counselling, at least 2 sessions with genetics counsellor and psychiatrist
2. Psychological assessment, exclude active suicidality, acute psychiatric illness
3. Support system confirmation, who will be present at disclosure?
4. Informed consent, voluntary, understanding of implications
5. Result disclosure, face-to-face, with support
6. Long-term psychological follow-up

B. Key Ethical Principles:

C. Special Populations:

Children:

• Predictive testing in asymptomatic minors is generally not recommended
• Reasons: No medical benefit in childhood, child cannot provide informed consent, right not to know must be preserved until adulthood
• Exception: If child has symptoms suggestive of juvenile HD

Prenatal testing:

• Available via chorionic villus sampling or amniocentesis
• Preimplantation Genetic Diagnosis (PGD): Selects unaffected embryos without revealing parental status (if parent chooses not to know their own result)

D. Psychological Responses to Positive Result:

• Acute grief, depression (highest suicide risk within 6 months of disclosure)
• Some experience relief ("end of uncertainty")
• Survivor guilt if sibling tests negative
• Changes in relationships, insurance, employment
• Requires sustained psychiatric follow-up

MODEL ANSWER 04

Q: Discuss psychosis in Parkinson's disease: clinical features, pathophysiology, and management. (8 marks)

Introduction

Psychosis affects 20–40% of Parkinson's disease (PD) patients over the disease course and represents one of the most challenging neuropsychiatric complications. It is a leading cause of caregiver burden and nursing home placement.

1. Clinical Features (3 marks)

PD psychosis presents on a spectrum:

Minor phenomena (early, benign):

• Presence hallucinations: Sensing someone behind them
• Passage hallucinations: Brief peripheral movement
• Illusions: Misidentifying objects (faces in patterns, shadows as people)
• Patient retains insight

Major phenomena (later, problematic):

• Formed visual hallucinations (VH): Most characteristic feature
• People, animals, complete scenes
• Usually non-threatening initially ("friendly visitors")
• Insight may be lost progressively
• Delusions: Paranoid, persecutory; Othello syndrome (morbid jealousy), belief that partner is unfaithful
• Auditory hallucinations: Less common; when prominent, consider DLB

Key clinical point: Unlike primary psychosis (schizophrenia), PD hallucinations typically occur in clear consciousness with intact insight initially.

2. Pathophysiology (2 marks)

• Cortical Lewy body pathology, extension to visual cortex and limbic areas
• Serotonergic dysfunction, 5-HT2A receptor dysregulation (visual cortex)
• Dopaminergic overstimulation, iatrogenic (dopaminergic medications activate mesolimbic receptors → hallucinations)
• Cholinergic deficit, especially in PDD (ACh deficit contributes to psychosis as in DLB)
• REM sleep behaviour disorder, may represent a continuum with visual hallucinations
• Visual impairment, impaired visual processing contributes

3. Risk Factors

• Dementia (strongest predictor)
• Higher dopaminergic medication dose
• Advanced disease, older age
• Visual impairment
• Sleep disturbance, depression, polypharmacy
• Anticholinergic medications

4. Management, Step-Wise (3 marks)

Step 1, Address reversible causes:

Reduce/discontinue medications in order of decreasing risk:

Anticholinergics → Amantadine → MAO-B inhibitors → Dopamine agonists → COMT inhibitors → Reduce levodopa (last resort)

Treat: UTI, constipation, pain, dehydration (frequent triggers in elderly)

Optimise: Sleep, correct visual impairment

Step 2, Antipsychotic selection:

Clozapine mechanism in PD: High affinity for D4 receptors, minimal D2 affinity → antipsychotic effect without blocking the dopamine required for motor function

MODEL ANSWER 05

Q: Describe the psychiatric manifestations of multiple sclerosis. Discuss pseudobulbar affect in detail. (8 marks)

Introduction

Multiple sclerosis (MS) is a chronic autoimmune demyelinating CNS disease with extensive neuropsychiatric manifestations. The lifetime prevalence of significant psychiatric disorder in MS exceeds that of any other neurological condition.

1. Psychiatric Manifestations of MS (4 marks)

a) Depression (50% lifetime prevalence):

• Most common psychiatric manifestation
• Mechanisms: Demyelination of limbic/frontal tracts, pro-inflammatory cytokines, interferon-beta therapy (IDO pathway, tryptophan depletion), psychosocial burden, steroid effects
• Interferon-induced depression: 20–30%; switch to glatiramer acetate or natalizumab; prophylactic SSRIs for high-risk patients
• Treatment: SSRIs (sertraline most studied in MS), CBT, aerobic exercise

b) Anxiety (36%):

• Generalised anxiety, panic disorder, social anxiety
• Often underdiagnosed and undertreated
• SSRIs/SNRIs, CBT

c) Cognitive Impairment (40–65%):

• Processing speed (most sensitive, Symbol Digit Modalities Test)
• Working memory, episodic learning
• Correlates with brain atrophy (grey matter > white matter lesion volume)
• Assessment: BICAMS (Symbol Digit Modalities Test + CVLT + BVMTR)

d) Pseudobulbar Affect (10%): (detailed below)

e) Fatigue (90%):

• Most common symptom overall
• Contributes to depression, cognitive complaints
• Treatment: Amantadine, modafinil, CBT for fatigue

f) Euphoria Sclerotica (historically described, largely a myth):

• Historical concept of inappropriate cheerfulness in MS
• Modern understanding: True pathological euphoria is rare (<5%)
• What was described was largely: cognitive impairment (reduced insight), pseudobulbar laughing (misinterpreted), selection bias
• Depression, not euphoria, is the dominant mood disturbance in MS

2. Pseudobulbar Affect (PBA) (4 marks)

Definition:

PBA (also: pathological laughing and crying, involuntary emotional expression disorder, IEED) is a neurological condition characterised by sudden, involuntary, uncontrollable episodes of laughing or crying that are disproportionate to, or inconsistent with, the underlying emotional state.

Key distinguishing features:

• No voluntary control over episodes
• Expression may NOT match inner feelings (patient may cry without feeling sad; laugh without feeling happy)
• Episodes triggered by mild, often non-emotional stimuli
• Abrupt onset and offset
• Patient retains awareness that the expression is abnormal

Prevalence in neurological conditions:

MS (10%), ALS/MND (50%), stroke (20%), TBI, PD, HD

Pathophysiology:

Disruption of corticobulbar (corticopontocerebellar) pathways, prefrontal cortex normally inhibits brainstem emotional expression circuits. Demyelination of these pathways in MS → release of brainstem from cortical inhibition → involuntary emotional expression

Differentiation from depression:

Differentiation from BPD/mania:

• In emotional lability of BPD/mania, the patient feels the emotion that is expressed, full emotional experience is present
• In PBA, the motor-expressive output is dissociated from the subjective emotional state

Treatment:

• Dextromethorphan/Quinidine (Nuedexta): FDA-approved for PBA specifically; acts on sigma-1 and NMDA receptors; effective
• SSRIs: Rapid, dramatic response (often within days, unlike antidepressant effect for mood); citalopram, fluoxetine
• TCAs: Amitriptyline historically effective
• Response is rapid and often dramatic (unlike treatment of primary depression)

MODEL ANSWER 06

Q: Discuss the neuropsychiatric manifestations of SLE. What is the role of antiphospholipid antibodies? (8 marks)

Introduction

Neuropsychiatric SLE (NPSLE) encompasses 19 distinct syndromes (ACR 1999 classification) affecting both the CNS and PNS. The prevalence of NPSLE is 25–75% depending on case definitions, making neuropsychiatric complications among the most significant contributors to SLE morbidity.

1. NPSLE Classification and Key Manifestations (3 marks)

Central Nervous System:

• Acute confusional state (delirium), common, often multifactorial
• Cognitive dysfunction, 80% on formal testing; "lupus fog"; attention and processing speed affected
• Seizures (15–20%)
• Mood disorder, depression (most common), anxiety
• Psychosis (2–8%)
• Cerebrovascular disease (stroke/TIA)
• Chorea (rare but classical)
• Headache
• Demyelinating syndrome

Peripheral Nervous System:

• Mononeuropathy, polyneuropathy
• Cranial neuropathy, Guillain-Barre syndrome

2. Psychiatric Manifestations in Detail (3 marks)

Psychosis:

• Occurs in 2–8% of SLE patients
• May be the presenting feature of SLE, important to exclude SLE in new-onset psychosis in young women
• Critical differential: SLE psychosis vs steroid-induced psychosis

Depression:

• Most common psychiatric manifestation
• Mechanisms: Cytokines, anti-neuronal antibodies, cerebrovascular disease, HPA dysregulation
• Also consider steroid-induced depression (dose-dependent, prolonged use)
• SSRIs effective; address underlying disease activity

Cognitive Impairment:

• Correlates with antiphospholipid antibodies (see below)
• "Lupus fog", subjective cognitive complaints
• May worsen with disease flares

3. Antiphospholipid Syndrome (APS) and Neuropsychiatric Implications (2 marks)

APS occurs in ~30% of SLE patients. It involves antibodies (anticardiolipin, anti-β2-glycoprotein I, lupus anticoagulant) that cause thrombosis and pregnancy complications.

Neuropsychiatric consequences of APS:

• Stroke/TIA, most significant; recurrent strokes → vascular dementia
• Cerebral venous thrombosis, headache, papilledema, seizures
• Cognitive impairment, chronic small vessel disease and microinfarcts
• Chorea, direct antibody effect on basal ganglia
• Sneddon syndrome: Livedo reticularis + stroke

Mechanism of psychiatric symptoms:

• Antibody-mediated neuronal dysfunction (direct effect on neuronal antiphospholipid targets)
• Microthrombi → small vessel ischaemia → mood/cognitive effects
• HPA dysregulation

Treatment: Anticoagulation (warfarin, target INR 2–3 for thrombotic APS), hydroxychloroquine (protective effect on APS), immunosuppression for active SLE

MODEL ANSWER 07

Q: Describe neurosyphilis: classification, clinical features of General Paresis of the Insane, and treatment. (8 marks)

Introduction

Neurosyphilis refers to infection of the CNS by Treponema pallidum. While largely preventable with early penicillin treatment, it remains clinically relevant, particularly in HIV co-infected individuals, where the risk is 7–10 times higher and progression more rapid.

1. Classification of Neurosyphilis (2 marks)

2. General Paresis of the Insane (GPI) (3 marks)

GPI results from diffuse spirochetal invasion of cortical parenchyma, causing progressive encephalopathy with prominent psychiatric and cognitive features.

Mnemonic: PARESIS

• P, Personality change (often first sign, irritability, disinhibition)
• A, Affect (lability, depression, or manic elevation)
• R, Reflexes (hyperreflexia)
• E, Eye (Argyll Robertson pupil)
• S, Sensorium (altered consciousness, confusion)
• I, Intellect (progressive dementia, frontal and global)
• S, Speech (dysarthria, tremulous speech)

Psychiatric features:

• Personality change is often the initial feature, coarsening of personality, irritability, poor judgment
• Grandiose delusions: Classically described ("I am Napoleon, I am God, I own unlimited wealth"), memorable but less common than depression
• Depression: More common than grandiosity in modern series
• Mania: Elevated mood, grandiosity, disinhibition
• Progressive dementia, frontal executive dysfunction → global impairment

Argyll Robertson Pupil:

• Small, irregular, bilateral pupils
• Accommodation reflex PRESERVED
• Light reflex LOST
• Mnemonic: "Prostitute's pupil, accommodates but does not react"
• Lesion: Pretectal nucleus of dorsal midbrain

3. Diagnosis (1 mark)

• CSF VDRL, most specific test for neurosyphilis (70% sensitivity)
• FTA-ABS serum, screening; highly sensitive
• CSF: Lymphocytic pleocytosis, elevated protein
• CSF RT-QuIC not applicable (CJD test)

4. Treatment (2 marks)

• Aqueous crystalline benzyl penicillin G: 18–24 million units/day IV in divided doses × 10–14 days (standard of care)
• Alternative: Procaine penicillin 2.4 million units IM/day + probenecid 500mg QID × 10–14 days
• Penicillin allergy: Desensitise if possible; ceftriaxone IV 2g/day × 10–14 days (less evidence)
• Jarisch-Herxheimer reaction: Fever, rigors, hypotension 2–8 hours after first dose; pre-treat with paracetamol; continue penicillin
• HIV co-infection: Same regimen; higher relapse rate, CSF follow-up at 6-month intervals

MODEL ANSWER 08

Q: Discuss Creutzfeldt-Jakob disease: clinical features, diagnosis, and types. (6 marks)

Introduction

Creutzfeldt-Jakob disease (CJD) is the most common human prion disease, belonging to the group of Transmissible Spongiform Encephalopathies (TSEs). It is caused by misfolded prion proteins (PrP^Sc) that propagate by converting normal cellular prion protein (PrP^C). The defining neuropathological feature is spongiform vacuolation of the neuropil.

1. Types of CJD (2 marks)

2. Clinical Features, Sporadic CJD (2 marks)

• Median age: 65 years; median survival: 4–6 months
• Rapidly progressive dementia, weeks, not months
• Cerebellar ataxia
• Visual disturbances (cortical blindness, visual hallucinations)
• Myoclonus, stimulus-sensitive, episodic (characteristic)
• Pyramidal and extrapyramidal signs
• Akinetic mutism, late stage, poor prognostic sign

Variant CJD distinguishing features:

• Young patients (mean 29 years)
• Psychiatric and sensory symptoms dominate early (depression, anxiety, dysaesthesias)
• Neurological features develop later (ataxia, involuntary movements, dementia)
• Longer course (~13 months)

3. Diagnosis (2 marks)

WHO Diagnostic Criteria (sCJD):

• Definite: Neuropathological confirmation
• Probable: Rapidly progressive dementia + 2 of (myoclonus, visual/cerebellar, pyramidal/extrapyramidal, akinetic mutism) + EEG PSWC or positive 14-3-3 in CSF
• Possible: Progressive dementia + 2 of 4 features, duration <2 years, no EEG/CSF support

MODEL ANSWER 09

Q: Discuss impulse control disorders in Parkinson's disease. What is dopamine dysregulation syndrome? (6 marks)

Introduction

Impulse Control Disorders (ICDs) are a significant and under-recognised complication of dopamine agonist therapy in Parkinson's disease. The DOMINION study (Weintraub, 2010) found a prevalence of 13.6% in PD patients on dopamine agonists, representing a major quality-of-life and safety concern.

1. Types of ICD in PD (2 marks)

• Pathological gambling, most common; financial devastation
• Hypersexuality, causes marital distress; may present as paraphilias
• Compulsive eating/binge eating, weight gain; typically carbohydrate craving
• Compulsive shopping (oniomania), financial consequences
• Punding, complex stereotyped, repetitive, purposeless behaviours (sorting, collecting, dismantling objects); distinct from classical ICD
• Hobbyism, excessive engagement in a hobby (often related to punding)

2. Mechanism (2 marks)

ICDs in PD are caused by overstimulation of the mesolimbic (reward) dopamine pathway by dopamine agonists.

Key pharmacological concept: Dopamine agonists (pramipexole, ropinirole, rotigotine) have preferential affinity for D3 receptors located in the ventral striatum (nucleus accumbens, reward circuitry). The dorsal striatum (motor function) may be appropriately medicated, but the ventral striatum (reward/impulsivity) becomes over-dosed.

Risk factors:

• Dopamine agonist use (pramipexole > ropinirole > rotigotine)
• Higher agonist doses
• Younger age of PD onset
• Male sex
• Personal/family history of substance use or gambling
• Novelty-seeking personality premorbidly

3. Dopamine Dysregulation Syndrome (DDS) (2 marks)

DDS is distinct from ICD, it represents an addiction to dopaminergic medication itself.

Core features:

• Compulsive, excessive use of dopaminergic medications beyond what is required for motor control
• Drug-seeking behaviour, hoarding medications, forging prescriptions
• Mood fluctuations: extreme dysphoria in OFF state (drives excessive dosing), hypomanic/euphoric in ON state
• Aggression and hostility when medication is withheld
• Hedonistic homeostatic dysregulation, dysphoric OFF state is the primary driver
• May include paranoia and psychosis during excessive ON states

Mechanism: The OFF state dysphoria (low dopamine) creates a negative reinforcement loop → patient takes more medication to relieve dysphoria → creates over-ON states with euphoria → positive reinforcement

Risk factors: Prior substance use disorder, impulsive personality traits, younger onset PD

Management:

• Extremely difficult, reducing medication causes severe motor symptoms
• Psychiatric support, family psychoeducation
• Opioid antagonists (naltrexone), limited evidence
• Deep brain stimulation (DBS): Can reduce total medication requirement → may break the cycle
• Motivational interviewing, addiction-focused psychotherapy

MODEL ANSWER 10

Q: Describe the neuropsychiatric manifestations of renal failure. Discuss special considerations for prescribing psychotropics in renal impairment. (6 marks)

Introduction

Renal failure produces neuropsychiatric manifestations through accumulation of uremic toxins, electrolyte disturbances, fluid shifts, and co-occurring psychological burden of chronic illness. The spectrum ranges from subtle personality changes in mild uremia to delirium and coma in acute severe uraemia.

1. Neuropsychiatric Manifestations (3 marks)

Uremic Encephalopathy (graded by severity):

• Mild: Fatigue, cognitive slowing, personality change, irritability, insomnia
• Moderate: Confusion, impaired concentration, restless legs, myoclonus, asterixis
• Severe: Delirium, hallucinations, seizures, stupor, coma
• Asterixis (flapping tremor), also seen in hepatic failure, hypercapnia; bilateral, metabolic

Dialysis-Related Neuropsychiatric Conditions:

Psychological burden:

• Dependency on dialysis machine (3× weekly)
• Sexual dysfunction, body image changes
• Career and relationship impact
• PTSD-like presentations

2. Psychotropic Prescribing in Renal Impairment (3 marks)

Drugs to AVOID or use with extreme caution:

Relatively safe (hepatic metabolism):

• Olanzapine, quetiapine, hepatic; generally safe in CKD
• Lorazepam, glucuronidation; safer than other benzodiazepines in CKD
• SSRIs (escitalopram, sertraline, fluoxetine), hepatic; generally safe; monitor for hyponatraemia (can worsen in renal failure)
• Mirtazapine, hepatic; also useful for sleep and appetite in dialysis patients
• Valproate, hepatic; reduce dose if hypoalbuminaemia (affects protein binding)

General principles:

• Start low, go slow
• Monitor drug levels where applicable
• Watch for accumulation after dialysis (some drugs are dialysed; others are not)
• Benzodiazepines: Short-acting, oxazepam preferred (glucuronidation)
• Coordinate with nephrology team

MODEL ANSWER 11

Q: Discuss depression in HIV. How does it differ clinically from primary MDD and how should it be treated? (6 marks)

Introduction

Depression is the most common psychiatric comorbidity in HIV, with a prevalence of 30–60%, three to four times higher than the general population. Its management has direct implications for ART adherence, viral suppression, and overall HIV outcomes.

1. Aetiology of Depression in HIV (2 marks)

Multiple converging mechanisms:

• Direct neurobiological: HIV viral proteins (gp120, Tat) disrupt monoamine systems; HPA axis dysregulation (chronic immune activation); cytokine-induced depression (TNF-α, IL-1β, IFN-γ activate IDO pathway → tryptophan depletion → serotonin deficit)
• ART-related: Efavirenz (NNRTI), depressogenic in 10–15% via CYP2B6-mediated effects; zidovudine (fatigue)
• CNS disease: Direct CNS HIV involvement (HAND)
• Psychosocial: Stigma, discrimination, loss of employment, bereavement, sexual identity issues, relationship disruption
• Substance use: Bidirectional relationship, depression drives use, use causes depression
• Nutritional: Vitamin B12, folate deficiency (common in HIV)

2. Clinical Differences from Primary MDD (2 marks)

Assessment recommendation: Prioritise psychological/cognitive criteria (hopelessness, worthlessness, anhedonia, poor concentration) over somatic criteria when assessing depression in HIV. PHQ-9 and MADRS are preferred.

3. Treatment (2 marks)

Pharmacological:

• SSRIs first-line: Sertraline, escitalopram (good tolerability, minimal drug interactions)
• Fluoxetine: Effective but inhibits CYP2D6 and CYP3A4, check ART interactions
• SNRIs: Venlafaxine effective
• TCAs: Effective but anticholinergic burden, cardiac side effects, and drug interactions limit use
• MAOIs: Avoid, interactions with ART and dietary restrictions
• Drug interactions: Ritonavir (CYP3A4 inhibitor) dramatically increases levels of many antidepressants, dose adjust
• Treat efavirenz-induced depression: Switch to dolutegravir-based regimen

Psychotherapy:

• CBT and IPT have the strongest evidence base in HIV depression
• Adherence counselling integrated with psychotherapy improves both depression and ART adherence

Key clinical point: Treating depression in HIV is not just about mood, it directly improves ART adherence. An OR of 3.4 for non-adherence has been associated with untreated depression. This makes depression treatment a priority in HIV management, not an afterthought.

MODEL ANSWER 12

Q: Write short notes on: (a) Efavirenz and neuropsychiatric side effects, (b) HIV testing and counselling. (5 marks each)

a) Efavirenz and Neuropsychiatric Side Effects (5 marks)

Introduction:

Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that was for many years the backbone of first-line ART. Despite its efficacy, neuropsychiatric side effects occur in 40–52% of patients, making it one of the most neuropsychiatrically active ART drugs.

Mechanism:

• GABA-A receptor agonism (particularly at α1β2γ2 subunits) → sedation, unusual dreams
• CB1 receptor inverse agonism (cannabinoid receptor) → psychoactive effects
• Inhibits CYP2B6 (its own primary metabolic enzyme), CYP3A4, CYP2C9
• Polymorphisms in CYP2B6 (slow metaboliser genotype, common in South Asian and African populations) → higher plasma levels → more CNS effects

Neuropsychiatric effects:

• Sleep disturbances: Insomnia, hypersomnia, vivid/disturbing/nightmares, most common (up to 50%)
• Cognitive symptoms: Difficulty concentrating, memory problems ("mental fog")
• Mood effects: Depression (10–15%), emotional lability, dysphoria
• Anxiety: Panic attacks, generalised anxiety
• Psychosis: Hallucinations, paranoid delusions (rare but well-documented)
• Mania: Manic episodes reported, especially with higher plasma levels

Time course:

• Most severe in first 2–4 weeks of therapy
• Usually improve by 6–8 weeks (accommodation effect)
• Some patients have persistent symptoms

Management:

• Timing: Take at night (reduces wakeful neuropsychiatric symptoms)
• Monitoring: Screen at each visit in first 3 months
• Switch to dolutegravir-based regimen: Dolutegravir (INSTI) has a much superior neuropsychiatric profile; now preferred globally (WHO 2019 guidelines)
• For acute psychosis: Low-dose antipsychotic + switch ART
• For depression: SSRI + evaluate need to switch ART

b) HIV Testing and Counselling (5 marks)

Principles:

HIV testing and counselling (HTC) follows the 5 Cs: Consent, Confidentiality, Counselling, Correct results, Connection (to care).

Types of HTC:

Components of VCT:

Pre-test counselling:

• Risk assessment (transmission routes, exposures)
• Explanation of test (what it measures, window period)
• Implications of positive/negative result
• Coping strategies
• Informed consent, voluntary, without coercion
• Support system identification

HIV Testing:

• 4th generation ELISA: Detects p24 antigen + anti-HIV antibodies; window period ~18 days
• 3rd generation ELISA: Detects antibodies only; window period ~22 days
• NAAT (Nucleic Acid Amplification Test): Detects viral RNA; window period ~10 days; most sensitive in acute HIV
• Confirmatory: Western Blot or Line Immunoassay (in reactive ELISA)
• Rapid tests: Point-of-care; useful in resource-limited settings

Post-test counselling:

Negative result:

• Explain window period (if recent exposure, retest at 6 weeks, 3 months)
• Prevention counselling (safer sex, PrEP if high risk)
• Address relief/disappointment reactions

Positive result:

• Deliver in person, in private
• Immediate supportive counselling
• Assess suicide risk
• Explain significance (positive = AIDS diagnosis)
• Disclosure guidance (to partner, family)
• Linkage to care: ART clinic, CD4 count, viral load
• Address stigma concerns

Special populations:

• PPTCT (Prevention of Parent-to-Child Transmission): Routine opt-out testing in all pregnant women; ART for mother + infant prophylaxis
• Adolescents: Confidential testing; involve trusted adult where possible
• Post-exposure prophylaxis (PEP): Within 72 hours of exposure; 28-day course

MODEL ANSWER 13

Q: Discuss the psychiatric features of Wilson's disease and its relevance to psychiatry. (5 marks)

Introduction

Wilson's disease (hepatolenticular degeneration) is an autosomal recessive disorder of copper metabolism (ATP7B gene, chromosome 13) causing copper accumulation in liver, brain (lenticular nucleus), and cornea. It is clinically significant to psychiatry because 50% of patients present with neuropsychiatric symptoms, and psychiatric presentations can precede hepatic or neurological signs by years.

1. Psychiatric Features (3 marks)

Clinical trap: Psychiatric presentation of Wilson's disease in a young person is frequently misdiagnosed as primary psychiatric illness (schizophrenia, BPD, or mood disorder). Antipsychotics or antidepressants may be started without investigating the underlying cause. This delays copper-chelation therapy and allows irreversible neurological damage.

2. When to Suspect Wilson's Disease in a Psychiatric Patient (1 mark)

• Young patient (<40 years) with psychiatric symptoms + movement disorder
• Psychiatric symptoms + liver disease (elevated LFTs, cirrhosis)
• Psychiatric symptoms not responding to standard treatment
• Tremor (especially wing-beating/rubral), dysarthria, ataxia
• Kayser-Fleischer rings on slit-lamp examination (>99% sensitivity in neurological Wilson's)

3. Diagnosis and Treatment (1 mark)

• Serum ceruloplasmin: Low (<20 mg/dL)
• 24-hour urinary copper: High (>100 μg/day)
• Liver biopsy: Copper quantification (>250 μg/g dry weight)
• Slit-lamp: KF rings

Treatment:

• D-penicillamine (chelation), first-line
• Trientine, chelation, fewer side effects
• Zinc, maintenance therapy (blocks intestinal absorption)
• Psychiatric symptoms often improve with copper chelation, treat the cause

MODEL ANSWER 14

Q: Describe the management of depression in Parkinson's disease. (5 marks)

Introduction

Depression affects 40–50% of Parkinson's disease patients and is the most common neuropsychiatric symptom of PD. It is not simply reactive, it has a specific neurobiological substrate involving degeneration of noradrenergic (locus coeruleus) and serotonergic (raphe nuclei) systems, often preceding motor symptoms by years.

1. Assessment (1 mark)

• Use instruments that minimise somatic overlap: GDS-15 (Geriatric Depression Scale), HDRS (Hamilton Depression Rating Scale), MADRS
• BDI has somatic items that overlap with PD motor symptoms, less ideal
• Distinguish from: apathy (no negative affect in apathy), cognitive impairment, side effects of medications

2. Pharmacological Management (3 marks)

A. SSRIs (first-line):

• Paroxetine, escitalopram, sertraline, most studied
• Generally well-tolerated
• Paroxetine: Anticholinergic effects may slightly worsen motor symptoms in some patients, use cautiously in advanced PD
• Important interaction: Selegiline/Rasagiline (MAO-B inhibitors used for motor symptoms) + SSRIs → serotonin syndrome risk, use with caution or avoid combination

B. SNRIs:

• Venlafaxine: Controlled trial evidence in PD; useful for concurrent anxiety

C. TCAs:

• Nortriptyline: Evidence from RCTs; effective but anticholinergic burden risks (confusion, urinary retention, falls, constipation)
• Desipramine: Less anticholinergic; used in selected patients
• Generally not first-line due to side effect profile in elderly

D. Dopaminergic approach:

• Pramipexole (dopamine agonist): Demonstrated antidepressant effects beyond its motor benefits; particularly useful when motor under-treatment is contributing
• Optimising dopaminergic therapy first (preventing OFF periods) often improves depression

E. ECT:

• Effective for severe or treatment-resistant PD depression
• Bonus: Temporarily improves motor symptoms (motor and mood effects of ECT in PD)
• Consider in severe cases, particularly with psychomotor retardation

3. Non-Pharmacological Management (1 mark)

• Cognitive Behavioural Therapy (adapted for PD): Evidence-based; addresses illness-related themes, helplessness, grief
• Aerobic exercise: Antidepressant effects + potential neuroprotective benefits
• Social support and peer groups: Combat isolation
• Psychoeducation for patient and caregivers
• Treat concurrent pain and motor fluctuations (improve mood indirectly)

MODEL ANSWER 15

Q: Write a short note on Hepatic Encephalopathy: psychiatric aspects and prescribing considerations. (5 marks)

Introduction

Hepatic encephalopathy (HE) is a spectrum of neuropsychiatric dysfunction arising from hepatic failure, characterised by accumulation of ammonia and other neuro-toxic substances, activation of GABA-ergic pathways, and neuroinflammation.

1. Neuropsychiatric Manifestations (2 marks)

West Haven Criteria:

Psychiatric presentations of HE:

• Confusion/delirium (most common psychiatric presentation)
• Personality change in chronic liver disease (covert HE)
• Anxiety and sleep reversal (early)
• Depression in cirrhosis (multifactorial, HE, chronic illness, substance withdrawal)
• Asterixis, bilateral flapping tremor of outstretched hands (also in renal failure and hypercapnia)

2. Mechanism (1 mark)

• Elevated ammonia → astrocyte swelling, glutamate dysregulation
• Accumulation of GABA agonists (endogenous benzodiazepine-like substances) → increased GABAergic tone → sedation
• Manganese deposition in basal ganglia → parkinsonian features
• Inflammatory cytokines → neuroinflammation
• False neurotransmitters (octopamine, phenylethanolamine) displace dopamine/noradrenaline

3. Psychotropic Prescribing in Liver Failure (2 marks)

Drugs to AVOID:

• Valproate: Hepatotoxic; also raises ammonia levels independently, contraindicated
• Chlorpromazine, TCAs: Highly sedating; lower seizure threshold; highly protein-bound (accumulate in hypoalbuminaemia)
• Chlordiazepoxide, diazepam: Long-acting benzodiazepines, accumulate in liver failure; precipitate deeper HE

Relatively safe:

• Lorazepam, oxazepam, temazepam: Glucuronidation only (not oxidative metabolism), safer in cirrhosis; however, all benzodiazepines can precipitate HE
• Haloperidol (low dose): Reasonable for acute agitation/delirium in HE; avoid high doses
• Quetiapine: Hepatic; use lowest effective dose
• SSRIs (escitalopram, citalopram): Generally safe; avoid fluvoxamine (hepatic); monitor LFTs

General approach:

• Reduce doses significantly in cirrhosis (first-pass metabolism reduced)
• Monitor ammonia levels when adding medications
• Avoid sedatives wherever possible, precipitate deeper HE
• Treat the underlying cause of HE first (lactulose, rifaximin)

Mnemonics & Memory Tricks

HIV, Parkinson's Disease & Other Neuropsychiatry

MNEMONIC 01: HAND Classification

"ANI Makes Dementia"

Progression of HAND across three stages

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Quick test: What two features distinguish MND from ANI? (Answer: Same cognitive impairment, but MND has MILD functional impairment of IADLs)

MNEMONIC 02: IHDS Components

"Tap, Tap, Remember" (TTR)

Three components of the International HIV Dementia Scale

• T, Tapping (motor speed): Alternating index/middle finger tapping × 5 seconds
• T, Tapping sequence (psychomotor speed): Sequential hand movements
• R, Recall: 4-word list recall at 2 minutes

MNEMONIC 03: Opportunistic Infections in HIV by CD4 Count

"Terrible PCP Comes, MACs Attack"

CD4 thresholds for major OIs, descending order

Full mnemonic expansion:

• Terrible = <500, Thrush, TB reactivation
• PCP = <200, Pneumocystis, first serious OI
• Comes = <100, Cryptococcus, Cryptosporidiosis
• MACs = <50, MAC, CMV, most severe OIs

MNEMONIC 04: Efavirenz CNS Side Effects

"DAMN VIVID"

Neuropsychiatric side effects of Efavirenz

• D, Dreams (vivid, disturbing, nightmares)
• A, Anxiety
• M, Mania / Mood changes
• N, Nightmares / sleep disturbance
• V, Vivid hallucinations (visual)
• I, Insomnia
• V, Vertigo / dizziness
• I, Impaired concentration
• D, Depression / dysphoria

MNEMONIC 05: Antipsychotics in Parkinson's Disease

"Can Quetiapine Please? Olanzapine Ruins Haloperidol"

C-Q-P vs O-R-H: Safe vs Unsafe

SAFE:

• C, Clozapine (gold standard, low dose, D4 > D2, no motor worsening)
• Q, Quetiapine (most commonly used, weaker evidence)
• P, Pimavanserin (FDA-approved 2016, 5-HT2A inverse agonist, no D2 blockade)

UNSAFE:

• O, Olanzapine (contraindicated, significant motor worsening)
• R, Risperidone (avoid, D2 blockade worsens PD)
• H, Haloperidol (avoid, severe EPS in PD)

Quick test: What is the mechanism of pimavanserin that makes it safe in PD? (Answer: Selective 5-HT2A inverse agonist, no dopamine antagonism whatsoever)

MNEMONIC 06: General Paresis of the Insane

"PARESIS"

Classic mnemonic for features of GPI (neurosyphilis)

• P, Personality change (first symptom, coarsening, irritability)
• A, Affect (lability, depression, mania)
• R, Reflexes (hyperreflexia, UMN signs)
• E, Eye (Argyll Robertson pupil, accommodates but does not react)
• S, Sensorium (confusion, disorientation)
• I, Intellect (progressive dementia)
• S, Speech (dysarthria, tremulous speech)

MNEMONIC 07: Argyll Robertson Pupil vs Holmes-Adie

"AR: Accommodates, Refuses light"

"HA: Has Atony (responds slowly)"

MNEMONIC 08: Huntington's Disease Genetics

"40-40 Rule and CAG Anticipation"

HD genetics in one frame

The 40-40 Rule: ≥40 repeats → 100% penetrance | Juvenile HD → >60 repeats

Anticipation: CAG repeats expand each generation, especially with paternal transmission.

MNEMONIC 09: Anti-NMDAR Encephalitis Clinical Phases

"Prodrome → Psych → Neuro → Recovery" = "Pretty Psychiatrists Never Recover"

(Self-deprecating but memorable)

Quick test: What is the EEG finding highly specific for anti-NMDAR encephalitis? (Answer: Extreme delta brush, present in ~30%)

MNEMONIC 10: Cryptococcal Meningitis in HIV

"CAN FEEL ILL" (CSF findings + clinical)

Clinical:

• C, Chronic/subacute onset (weeks)
• A, Afebrile in many (poor inflammatory response)
• N, No meningismus sometimes

CSF:

• F, Few cells (normal or <20 WBC)
• E, Elevated opening pressure (>200 mm H2O in 75%)
• E, Elevated protein (mild)
• L, Low glucose

Tests:

• I, India ink positive (70–80%)
• L, Low CD4 (<50 usually)
• L, Latex agglutination/CrAg >95% sensitivity

MNEMONIC 11: Wernicke's Triad and Treatment Rule

"The COAt" and "GIVE THIAMINE BEFORE GLUCOSE"

Wernicke's Triad:

• C, Confusion/delirium (80%, most common; full triad only in 16%)
• O, Ophthalmoplegia/nystagmus/lateral gaze palsy (25%)
• A, Ataxia (gait) (23%)

Pathology locations: Mammillary bodies (classic), periaqueductal gray, medial thalamus

Critical treatment rule:

Korsakoff triad:

• A, Anterograde amnesia (severe, cannot form new memories)
• R, Retrograde amnesia (with temporal gradient)
• C, Confabulation (unintentional gap-filling, ARC = Anterograde + Retrograde + Confabulation)

MNEMONIC 12: Impulse Control Disorders in PD

"PHECS" = All ICD Types in PD

• P, Pathological gambling (most common)
• H, Hypersexuality
• E, Eating compulsively (binge eating)
• C, Compulsive shopping
• S, Stereotyped/punding behaviours

Extra: DDS (Dopamine Dysregulation Syndrome) = addiction to the medication itself (compulsive overuse of levodopa/agonists beyond motor need).

MNEMONIC 13: Psychotropics to Avoid in Renal vs Hepatic Failure

"LEGAL" = Avoid in Renal | "VALCO" = Avoid in Hepatic

Avoid in RENAL failure, "LEGAL":

• L, Lithium (renally cleared; nephrotoxic)
• E, Eliminate gabapentin (renal clearance, dose reduce/avoid)
• G, G-line drugs: Amisulpride (renally cleared)
• A, Active metabolites accumulate: Risperidone (9-OH-risperidone renal)
• L, Long-acting benzodiazepines (accumulate; use oxazepam instead)

Avoid in HEPATIC failure, "VALCO":

• V, Valproate (hepatotoxic + raises ammonia)
• A, Amitriptyline/TCAs (accumulate, sedating)
• L, Long-acting benzodiazepines (diazepam, chlordiazepoxide)
• C, Chlorpromazine (hepatotoxic, accumulates)
• O, Oxidatively metabolised drugs (most psychotropics, switch to glucuronidated ones: lorazepam, oxazepam)

MNEMONIC 14: CJD Investigations

"MRI-EEG-3-QuIC"

The four investigations for CJD in order of use

For vCJD specifically:

• Pulvinar sign: T2 hyperintensity in posterior thalamus on MRI
• Tonsillar biopsy: PrP^Sc in lymphoid tissue, diagnostic ante-mortem for vCJD

MNEMONIC 15: HIV-Associated Mania vs Primary Bipolar Mania

"LICA": Features of HIV/AIDS Mania (Secondary Mania)

• L, Late-stage HIV (CD4 <200 typically)
• I, Irritability dominant (not euphoria, unlike primary mania)
• C, Cognitive impairment prominent (looks like disinhibited dementia)
• A, Absent family history of bipolar disorder

Contrast with primary mania:

• Euphoria more prominent
• Family history often present
• Earlier in HIV course or pre-dates HIV
• No progressive cognitive decline

MNEMONIC 16: Pseudobulbar Affect vs Emotional Lability

"PBA = Pathological BEHAVIOUR of Affect (dissociated from feeling)"

MNEMONIC 17: Dopamine Agonist ICDs vs DDS

"ICD = Directed OUTWARD | DDS = Directed INWARD"

ICDs (directed outward, reward-seeking behaviours):

• Gambling, sex, eating, shopping, punding
• Driven by D3/mesolimbic overstimulation
• Patient pursues external rewards compulsively

DDS (directed inward, drug-seeking):

• Addiction to the medication itself
• Patient pursues the drug (levodopa/agonist)
• Hoarding, forging, demanding
• Driven by OFF-state dysphoria (internal negative state → drug-seeking)

MNEMONIC 18: MS Psychiatric Features: "CAFE"

Psychiatric features of Multiple Sclerosis

• C, Cognitive impairment (40–65%; processing speed most sensitive)
• A, Affect (depression 50%, most common; interferon-induced variant)
• F, Fatigue (90%, most common symptom overall; not strictly psychiatric but drives depression)
• E, Emotional incontinence / pseudobulbar affect (10%)

Plus: Anxiety (36%), Euphoria sclerotica (historical myth, largely not real)

MNEMONIC 19: Autoimmune Encephalitis Antibodies Quick Reference

MNEMONIC 20: Wilson's Disease Red Flags in Psychiatry

"KAYSER-FLAG"

When to suspect Wilson's disease in a psychiatric patient:

• K, KF rings on slit-lamp (>99% in neurological Wilson's)
• A, Age <40 years with psychiatric presentation
• Y, Young adult with tremor + psychiatric symptoms
• S, Subcortical dementia pattern in young patient
• E, Elevated LFTs + psychiatric symptoms
• R, Refractory to standard psychiatric treatment

Flag = Investigate:

• Serum ceruloplasmin (LOW)
• 24-hour urinary copper (HIGH)
• Slit-lamp examination (KF rings)

RAPID RECALL TABLE: All Mnemonics at a Glance

High-Yield Comparisons

HIV, Parkinson's Disease & Other Neuropsychiatry

TABLE 01: HAND Staging: ANI vs MND vs HAD

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TABLE 02: PD Depression vs Primary MDD

TABLE 03: DLB vs PDD (Lewy Body Spectrum)

TABLE 04: Anti-NMDAR Encephalitis vs First-Episode Schizophrenia

TABLE 05: Huntington's Disease vs Other Causes of Choreiform Dementia

TABLE 06: NPSLE Classification, CNS vs PNS Manifestations

TABLE 07: Antipsychotic Safety in Special Neurological Populations

TABLE 08: Dementia Profiles: Subcortical vs Cortical

TABLE 09: Neurosyphilis Types Comparison

TABLE 10: Prion Disease Comparison: sCJD vs vCJD vs FFI vs Kuru

SUMMARY COMPARISON TABLE: Autoimmune Encephalitides

PYQ Frequency Analysis

HIV, Parkinson's Disease & Other Neuropsychiatry

SECTION 1: QUESTION FREQUENCY HEATMAP

By Topic Area

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SECTION 2: RECONSTRUCTED PREVIOUS YEAR QUESTIONS

2.1 LONG ANSWER QUESTIONS (10 marks)

PYQ-LA-01

Describe HIV-associated neurocognitive disorders (HAND). Discuss the staging, pathophysiology, assessment tools, and principles of management.

(10 marks, PG Paper IV pattern, 2019, 2022)

Examiner focus: Complete Antinori classification mandatory. IHDS scoring must be correct. Pathophysiology should cover both direct viral protein neurotoxicity AND macrophage-mediated injury. Management = ART optimisation first, then symptomatic.

Marks breakdown (suggested):

• Classification/staging: 3 marks
• Pathophysiology: 3 marks
• Assessment (IHDS + neuropsychological domains): 2 marks
• Management: 2 marks

Common mistakes:

• Stating HIV directly infects neurons (incorrect, no CD4 on neurons)
• Missing the functional impairment criterion that separates ANI from MND
• Omitting CPE score concept in management
• Confusing IHDS total (12) with cutoff (≤10)

PYQ-LA-02

A 28-year-old woman presents with acute onset psychosis, agitation, and bizarre behaviour over 2 weeks with no prior psychiatric history. Discuss the differential diagnosis, with emphasis on autoimmune encephalitis. How would you investigate and manage this case?

(10 marks, Exam pattern, 2021; PG exams 2023)

Examiner focus: Red flags for organic psychosis must be listed. Anti-NMDAR encephalitis clinical phases, psychiatric phase presenting first is THE teaching point. Investigation sequence and treatment protocol (first-line vs second-line immunotherapy) must be complete.

Marks breakdown:

• Differential diagnosis with organic vs primary: 2 marks
• Anti-NMDAR clinical profile (phases): 3 marks
• Investigations (CSF, EEG, MRI, antibodies, pelvic imaging): 2 marks
• Management (immunotherapy + teratectomy): 3 marks

Common mistakes:

• Not mentioning ovarian teratoma workup
• Confusing anti-NMDAR (young women, teratoma) with LGI1 (older men, hyponatraemia)
• Omitting the "extreme delta brush" EEG finding
• Not mentioning rituximab as second-line

PYQ-LA-03

Discuss the psychiatric manifestations of Huntington's disease. Describe the genetics, genetic counselling protocol, and ethical issues in predictive testing.

(10 marks, PG exams 2020; Exam pattern)

Examiner focus: CAG repeat numbers must be precise. Anticipation with paternal transmission. Psychiatric symptoms may precede motor, suicide risk in two specific periods. Genetic counselling must cover protocol AND ethical principles (autonomy, right not to know, children, PGD).

Marks breakdown:

• Genetics (CAG repeats, anticipation, inheritance): 2 marks
• Psychiatric manifestations (all types with prevalence): 4 marks
• Genetic counselling protocol: 2 marks
• Ethical issues: 2 marks

Common mistakes:

• Stating "dominant" without specifying full penetrance threshold (≥40 repeats)
• Missing anticipation via paternal transmission
• Not mentioning both high-risk periods for suicide
• Treating genetic counselling as just "pre-test and post-test" without the ethical substance

2.2 MEDIUM ANSWER QUESTIONS (8 marks)

PYQ-MA-01

Discuss psychosis in Parkinson's disease, clinical features, pathophysiology, and management. Which antipsychotic is contraindicated and why?

(8 marks, PG exams 2018, 2021; PG exams 2022)

Examiner focus: Spectrum from minor hallucinations to formed VH to delusions. Step-wise management. Antipsychotic table, clozapine vs quetiapine vs pimavanserin vs AVOID (olanzapine, risperidone, haloperidol). Mechanism of olanzapine contraindication (D2 blockade worsens PD motor).

High-yield points:

• Pimavanserin = 5-HT2A inverse agonist = no D2 blockade = no motor worsening = FDA 2016
• Clozapine = gold standard but requires WBC monitoring
• Olanzapine = contraindicated (not just "use caution")

PYQ-MA-02

Describe the neuropsychiatric manifestations of multiple sclerosis. Discuss pseudobulbar affect in detail.

(8 marks, PG exams 2020; PG exams 2022)

Examiner focus: Depression prevalence (50%) must be stated. Interferon-induced depression mechanism. Euphoria sclerotica = largely a myth, examiner expects you to say this, not accept the historical description. PBA: definition, pathophysiology (corticobulbar tract disruption), distinction from depression/BPD, treatment (SSRIs fast-acting; Nuedexta FDA-approved).

PYQ-MA-03

Discuss the classification and clinical features of neurosyphilis. Describe General Paresis of the Insane in detail.

(8 marks, PG exams 2017, 2019; TN MGR 2021)

Examiner focus: Classification table with timing (meningovascular 5–12y, GPI 15–20y, tabes 15–25y). PARESIS mnemonic for GPI. Argyll Robertson pupil, accommodates but does not react. Treatment = benzyl penicillin IV (not IM procaine for CNS disease as first-line). Jarisch-Herxheimer reaction.

PYQ-MA-04

Discuss depression in HIV infection, prevalence, aetiology, clinical features, and management.

(8 marks, PG exams 2016, 2023; PG exams 2020)

Examiner focus: Prevalence (30–60%). Multiple aetiologies (viral, ART, psychosocial, cytokine). Drug interactions with ART, ritonavir + SSRI. Efavirenz as cause of depression. Treat depression = improves ART adherence (this causal link is high-yield).

2.3 SHORT ANSWER QUESTIONS (5–6 marks)

PYQ-SA-01

Write a note on efavirenz and its neuropsychiatric side effects.

(5 marks, PG exams 2015, 2018, 2021; PG exams 2022)

Must include: Prevalence (40–52%), mechanism (GABA-A agonist + CB1 inverse agonist), list of effects (vivid dreams, depression, psychosis, mania, cognitive), time course (worst weeks 1–4, improves by 6–8 weeks), management (night dosing, switch to dolutegravir).

PYQ-SA-02

Describe HIV testing and counselling.

(5 marks, PG exams 2014, 2017, 2020)

Must include: 5 Cs (consent, confidentiality, counselling, correct results, connection to care). Types of HTC (VCT, PITC). Pre-test and post-test components. Window period. PPTCT. Linkage to care.

PYQ-SA-03

Write short notes on impulse control disorders in Parkinson's disease.

(5 marks, PG exams 2019; PG exams 2021; PG exams 2023)

Must include: Types (PHECS), prevalence (13.6% DOMINION study), mechanism (D3/mesolimbic, dopamine agonist preferential effect), risk factors, management (reduce/stop agonist first, then CBT/naltrexone). DDS as separate entity.

PYQ-SA-04

Write a note on Creutzfeldt-Jakob disease.

(5 marks, PG exams 2016, 2022)

Must include: Types (sCJD 85%, vCJD, fCJD, iatrogenic). sCJD clinical (rapidly progressive dementia, myoclonus, cerebellar, visual). Investigations (MRI DWI, EEG PSWC, 14-3-3, RT-QuIC). vCJD differences (young, psychiatric onset, pulvinar sign, tonsillar biopsy, no PSWC).

PYQ-SA-05

Write a note on Wilson's disease, psychiatric manifestations.

(5 marks, PG exams 2015, 2020)

Must include: ATP7B gene, AR inheritance, psychiatric features (personality change first, depression, psychosis, OCD), KF rings, diagnosis (ceruloplasmin, 24h copper, biopsy), treatment (D-penicillamine, trientine, zinc), clinical trap (misdiagnosed as primary psychiatric illness in young patients).

PYQ-SA-06

Describe the neuropsychiatric manifestations of SLE.

(5 marks, PG exams 2018; PG exams 2022)

Must include: ACR 1999, 19 NPSLE syndromes (12 CNS, 7 PNS). Key manifestations, cognitive dysfunction (most common), depression, psychosis (2–8%), seizures. APS and its neuropsychiatric role. Steroid-induced psychiatric effects vs SLE psychosis differential.

PYQ-SA-07

Short note on apathy in Parkinson's disease, distinguish from depression.

(5 marks, PG exams 2021; PG exams 2023)

Must include: Definition (quantitative reduction in motivated behaviour without mood disturbance). Prevalence (40–70%). Depression vs apathy distinction (negative affect present vs absent). Assessment (Starkstein Apathy Scale). Treatment (dopaminergic optimisation, rivastigmine, methylphenidate).

PYQ-SA-08

Write a note on REM Sleep Behaviour Disorder in Parkinson's disease.

(5 marks, PG exams 2022)

Must include: Definition (loss of normal REM atonia → dream enactment). Prodromal marker of PD (precedes motor symptoms by >10 years). Braak stage 1–2. Risk of injury. Polysomnography for diagnosis. Treatment (clonazepam 0.25–0.5 mg, melatonin high-dose).

2.4 VERY SHORT / SPOT QUESTIONS (2–3 marks)

SECTION 3: EXAMINER PATTERN ANALYSIS

3.1 Topics That Appear EVERY Exam Cycle

These topics have appeared at least once in nearly every examination sitting analysed:

1. HAND, classification, pathophysiology, IHDS
2. Psychiatric comorbidities in HIV, depression, mania (ART-associated), psychosis
3. PD psychosis and antipsychotic management, clozapine vs quetiapine vs pimavanserin vs avoid
4. Neurosyphilis/GPI, PARESIS mnemonic, Argyll Robertson pupil, treatment

3.2 Rising Frequency Topics (post-2018)

Topics showing increased exam frequency in recent cycles:

1. Anti-NMDAR encephalitis, now a standard 10-mark question
2. Impulse control disorders in PD + DDS, was rare pre-2018, now medium frequency
3. HD genetics + psychiatric features, increasing
4. Autoimmune encephalitis broadly, LGI1, CASPR2 appearing as short notes

3.3 Topics Likely Tested as Short Notes Only

These are tested but rarely as long-answer questions, prepare as 5-mark short notes:

• Fatal familial insomnia
• Kuru
• NPSLE classification
• REM sleep behaviour disorder
• Dopamine dysregulation syndrome
• Wilson's disease psychiatric features
• Dialysis dementia

3.4 Topics Never Asked as Standalone But Appear in Differentials

Prepare to mention these when relevant, not as primary answers:

• CNS lymphoma vs toxoplasmosis (PML distinction)
• Hashimoto's encephalopathy
• Wernicke-Korsakoff (usually in alcohol paper but may appear in context of nutritional/metabolic)

SECTION 4: STRATEGY NOTES BY QUESTION TYPE

For 10-mark HAND questions:

• Open with epidemiology sentence (50–70% lifetime neuropsychiatric burden)
• State cART era shift (HAD declined, milder forms predominant)
• Draw classification table, examiners award marks for visual organisation
• For pathophysiology: TWO mechanisms (direct viral proteins + macrophage bystander)
• For IHDS: state all 3 components, max score, cutoff, sensitivity/specificity
• Close with management hierarchy: ART first → CPE optimisation → symptomatic

For anti-NMDAR encephalitis:

• Lead with epidemiology (most common autoimmune encephalitis, Dalmau 2007)
• Clinical phases table is mandatory, use it
• State the trap: psychiatric phase presents to psychiatry ward FIRST
• Investigations: always mention pelvic ultrasound/CT for ovarian teratoma
• Treatment: name all steps, steroids + IVIG + plasmapheresis → rituximab + cyclophosphamide; teratectomy
• Prognosis: >80% improvement, 20–25% relapse

For PD psychosis antipsychotic questions:

• Present as a table, safe vs avoid
• Name pimavanserin with its mechanism (5-HT2A inverse agonist, 2016 FDA approval)
• Explain WHY olanzapine is contraindicated (D2 blockade, not just "avoid")
• Clozapine: mention WBC monitoring requirement (limits use despite being gold standard)

For HD genetic counselling:

• Follow the ethical principle structure: Autonomy → Beneficence → Non-maleficence → Justice
• Specifically address children (not tested, no benefit in childhood, cannot consent)
• Mention PGD as the option that avoids parental disclosure
• Two high-risk suicide periods: post-diagnosis + early motor phase

SECTION 5: INTEGRATED TOPIC MAP

Topics that commonly appear TOGETHER in one question:

SECTION 6: MARKS ALLOCATION CHEAT SHEET

When marks are not specified, use this allocation guide:

Rule: Never skip investigations and management, they are the most predictable marking zones.

Format tip: One table is worth 3 prose paragraphs in examiner perception. Use them.

SECTION 7: YEAR-WISE QUESTION TRACKING (Reconstructed)

Quick Review

HIV, Parkinson's Disease & Other Neuropsychiatry

VIGNETTE 01: The Psychiatric Ward Trap

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Presentation:

Priya, a 24-year-old postgraduate student with no prior psychiatric history, is brought by her parents after 12 days of increasingly bizarre behaviour. She had been well until 2 weeks ago when she developed a low-grade fever, headache, and malaise for 4 days, which her family attributed to examination stress.

Over the next week, she became agitated and suspicious, heard voices commenting on her actions, and developed the belief that her hostel warden was poisoning her food. She was initially seen by a psychiatrist at a private clinic who diagnosed first-episode schizophrenia and started risperidone 2 mg/day. She improved marginally but 3 days later began making repetitive chewing and tongue-thrusting movements and had a generalised tonic-clonic seizure.

On examination: GCS 13/15, oriented to person only, blood pressure 148/96 mmHg, heart rate 114 bpm, temperature 38.1°C. Repetitive orofacial movements noted. No focal neurological deficits.

Investigations:

• Blood: CBC normal, metabolic panel normal, LFTs normal
• MRI brain: Subtle T2/FLAIR hyperintensity in left hippocampus
• EEG: Diffuse delta slowing; brief runs of beta superimposed on delta ("extreme delta brush")
• CSF: 18 lymphocytes/mm3, protein 52 mg/dL, glucose normal, no organisms, Gram stain negative
• CSF anti-NMDAR IgG antibodies: Positive
• Pelvic ultrasound: Right ovarian cystic lesion 3.2 cm

Questions:

1. What is the diagnosis? What clues in the history point to it?
2. Why was risperidone an inadequate treatment? What are the risks of continuing it?
3. Outline the complete management plan.
4. What is the significance of the pelvic ultrasound finding?
5. What is "extreme delta brush" on EEG and what is its clinical significance?

Diagnosis: Anti-NMDA Receptor Encephalitis

Reasoning:

• Young woman, classic demographic
• Viral prodrome → psychiatric phase (psychosis, paranoia, agitation) → neurological phase (seizure, orofacial dyskinesias)
• CSF pleocytosis (lymphocytic) with normal glucose
• Extreme delta brush on EEG, highly specific (~30% of cases)
• MRI limbic involvement
• Confirmatory: CSF anti-NMDAR IgG positive
• Ovarian cystic lesion = likely teratoma (occurs in 50–60% of female cases)

Why risperidone was inadequate:

• Anti-NMDAR antibodies REDUCE NMDAR surface expression → dopamine disinhibition → psychosis
• Antipsychotics treat the symptom, not the cause
• Risperidone (D2 blocker) may exacerbate sedation and mask neurological deterioration
• No antipsychotic will reverse the antibody-mediated process

Management:

1. ICU monitoring, autonomic instability risk (BP, HR, temperature fluctuations); respiratory monitoring (hypoventilation possible)
2. First-line immunotherapy (simultaneously):
3. IV methylprednisolone 1g/day × 5 days
4. IVIG 2g/kg over 5 days
5. Consider plasmapheresis if no response
6. Antiepileptics for seizure control (levetiracetam preferred, no hepatic induction)
7. Gynaecology referral: Right ovarian cystic lesion → laparoscopic teratectomy (mandatory; dramatically improves outcomes)
8. Second-line if no improvement at 2–4 weeks: Rituximab 375 mg/m2 weekly × 4 doses ± cyclophosphamide
9. Symptomatic: Low-dose haloperidol or quetiapine for agitation if absolutely necessary; reassess after immunotherapy
10. Monitor: Antibody titres, functional recovery, ovarian pathology follow-up

Prognosis: >80% substantial recovery with treatment. Teratectomy is the single most impactful intervention.

Key Teaching Points:

• Anti-NMDAR encephalitis presents to psychiatry first, the psychiatric phase of 1–2 weeks precedes neurological signs
• Any "first-episode psychosis" in a young woman with fever, seizures, or movement disorder → send CSF for anti-NMDAR antibodies immediately
• The extreme delta brush on EEG is pathognomonic, learn to recognise it
• Teratoma is the tumour source of antigen, its removal accelerates recovery
• Do not anchor on schizophrenia, rapid onset, fever, normal premorbid function, seizures are all red flags

VIGNETTE 02: The Forgetful Professor

Presentation:

Ramesh, a 52-year-old college professor, is brought by his wife. Over the past 18 months, he has become increasingly forgetful, he misplaces items, forgets appointments, and repeats himself in conversations. His wife notes that he seems slower in his thinking and takes longer to grade papers. He has also become increasingly withdrawn and lacks his previous enthusiasm for teaching.

He has a 6-year history of HIV infection, currently on tenofovir/lamivudine/efavirenz. His last CD4 count (4 months ago) was 380 cells/μL, viral load undetectable. No history of OIs. No substance use.

On examination: Alert, cooperative. MMSE 24/30 (loses points on serial 7s, delayed recall, and complex commands). Finger-tapping slow bilaterally. Mild psychomotor slowing on clinical observation. No focal deficits, no tremor, no gait abnormality.

IHDS score: 9/12 (motor speed 3/4, psychomotor speed 3/4, memory recall 3/4)

Investigations:

• MRI brain: Mild generalised cerebral atrophy, no focal lesions, no white matter changes, no ring-enhancing lesions
• Comprehensive neuropsychological battery: Impairment in 3 domains (attention/working memory, psychomotor speed, executive function), all 1–1.5 SD below normative mean; IADL assessment shows difficulty managing complex financial tasks and calendar management

Questions:

1. What is the HAND diagnosis and why?
2. What cognitive domains are affected and why does this pattern suggest subcortical rather than cortical dementia?
3. Is efavirenz potentially contributing? What would you do?
4. Outline management.

Diagnosis: HAND, Mild Neurocognitive Disorder (MND)

Reasoning:

• Neuropsychological impairment in ≥2 domains (3 domains affected here), each ≥1 SD below normative mean
• Functional impairment is MILD, he can still work but struggles with complex IADLs (managing finances, calendar), meets MND criteria
• IHDS = 9/12 (≤10 = positive screen for HAD, but formal battery needed to characterise; formal battery confirms MND not HAD as ADLs preserved)
• Viral load undetectable, HIV not actively replicating, yet HAND persists (common in cART era, "residual neuroinflammation")

Why subcortical pattern:

• Retrieval memory deficit (not encoding, would respond to cues)
• Psychomotor slowing (hallmark of subcortical)
• Executive dysfunction prominent
• Relatively spared language, praxis, and naming
• Contrast with Alzheimer's: encoding failure, aphasia, apraxia, agnosia

Efavirenz contribution:

• Efavirenz causes CNS symptoms including cognitive impairment ("mental fog") in up to 40–52%
• May be CONTRIBUTING to cognitive symptoms
• Action: Switch efavirenz to dolutegravir, dolutegravir has better CNS profile and minimal cognitive side effects
• Reassess cognitive function 3 months after switch

Management:

1. ART optimisation: Switch efavirenz → dolutegravir; ensure viral suppression maintained
2. Calculate CPE score of current regimen, optimise CNS penetration
3. Treat contributing factors: Address depression (withdrawal, anhedonia), optimise sleep
4. Cognitive rehabilitation: Memory strategies, compensatory aids (structured routines, calendars, pill organisers)
5. Monitor with 6-monthly IHDS; annual formal neuropsychological testing
6. Occupational health assessment if work impairment progresses

Key Teaching Points:

• HAND in the cART era: viral load undetectable = no neurocognitive impairment (residual neuroinflammation continues)
• MND vs ANI distinction: both have cognitive impairment on testing; MND has MILD functional impact on IADLs
• Efavirenz is a modifiable contributor to cognitive symptoms in HIV, always review before attributing to HAND alone
• IHDS ≤10 is a screen, formal battery needed to stage HAND accurately

VIGNETTE 03: The Jealous Husband

Presentation:

Gopal, a 68-year-old retired bank manager with a 5-year history of Parkinson's disease, is brought by his daughter. He has been on levodopa/carbidopa 100/25 mg TDS and pramipexole 1 mg TDS for 3 years.

His daughter reports that over the past 6 months he has become increasingly suspicious of his wife, accusing her of being unfaithful and hiding money. He has questioned her about her phone calls, followed her when she leaves the house, and once struck her when she denied his accusations. He also admits to gambling online regularly over the past year, spending approximately ₹40,000–50,000 per month, something he had never done before. He has no insight into either behaviour.

On examination: Mild-to-moderate resting tremor, bradykinesia. MMSE 23/30 (mild impairment). Mood: guarded, suspicious. No auditory or visual hallucinations.

Current medications: Levodopa/carbidopa 100/25 TDS, pramipexole 1 mg TDS, pantoprazole, amlodipine.

Questions:

1. What are the two distinct neuropsychiatric problems in this vignette?
2. What is the common pharmacological mechanism linking both problems?
3. How would you manage the pathological jealousy specifically?
4. What is the risk of simply adding an antipsychotic without addressing the dopamine agonist?

Diagnosis:

1. Othello Syndrome (pathological/morbid jealousy), a delusional disorder with persecutory jealousy content
2. Pathological gambling, impulse control disorder (ICD) in PD

Common mechanism: Both are manifestations of mesolimbic dopamine overstimulation by pramipexole (dopamine agonist with high D3/D4 affinity in ventral striatum/reward circuit).

Management of pathological jealousy:

• Step 1: Reduce and discontinue pramipexole, primary intervention
• Taper slowly to avoid dopamine agonist withdrawal syndrome (dysphoria, anxiety, fatigue)
• Accept motor worsening; compensate with levodopa dose adjustment
• Step 2: Antipsychotic if delusion persists after agonist reduction
• Clozapine (first-line in PD, low dose 12.5–25 mg), does not worsen motor symptoms
• Quetiapine, alternative, no WBC monitoring needed
• DO NOT use olanzapine, risperidone, haloperidol, significant motor worsening in PD
• Step 3: Safety assessment, domestic violence risk; wife needs independent safety planning
• Step 4: Carer education, family must understand this is disease/medication-related, not moral failure

Risk of antipsychotic without addressing agonist:

• Will partially suppress the delusion but the underlying mesolimbic hyperdopaminergia continues
• Typical antipsychotics (haloperidol, risperidone) will cause severe EPS in PD
• Problem will recur or remain partially active
• Motor function will deteriorate significantly

Gambling management:

• Stop pramipexole (same mechanism, both ICD variants resolve with agonist reduction)
• Financial safeguards: Family takes over accounts
• CBT for gambling if residual behaviour persists after agonist reduction
• Naltrexone: Some evidence for ICD in PD; trial reasonable

Key Teaching Points:

• Othello syndrome + ICD in PD, same root cause (dopamine agonist), two clinical expressions
• Pimavanserin would be ideal for psychosis in PD (no D2 blockade) but not available in India, clozapine is the accessible gold standard
• Domestic violence assessment is mandatory when delusions involve infidelity accusations
• Always screen PD patients on agonists with the QUIP questionnaire (Questionnaire for Impulsive-Compulsive Disorders in PD)

VIGNETTE 04: The Missing Months

Presentation:

Suresh, a 58-year-old farmer with chronic alcohol use disorder (drinking ~180 mL of country liquor daily for 25 years), was admitted following a road traffic accident. He sustained no major injuries. During the hospital stay, he developed Wernicke's encephalopathy on day 3 (confusion, lateral gaze palsy, ataxia), which was treated with parenteral thiamine.

Six weeks later, he is reviewed at psychiatry OPD by his wife. The acute encephalopathy has resolved. However, his wife says he cannot remember anything that happened after 2015. He does not remember the accident, does not recognise the treating doctor despite meeting him multiple times, and yesterday told his wife about a "fishing trip he went on last week", which never happened. He can hold a brief conversation and remember things from the distant past (his childhood, his children's names, farming knowledge) but cannot recall what he had for breakfast.

On examination: Alert, conversational. Behaves normally in the consultation. When asked about the past week, gives plausible but incorrect accounts. Insists he is correct. MMSE 22/30 (loses marks on orientation to time/recent events and 3-word recall).

Questions:

1. What syndrome is this? Distinguish it from dementia.
2. Name and explain the three core cognitive features.
3. What is confabulation, is it lying?
4. What is the prognosis? What treatment options exist?

Diagnosis: Korsakoff's Syndrome (Chronic Wernicke-Korsakoff Syndrome)

Reasoning:

• Preceded by documented Wernicke's encephalopathy (treated with thiamine)
• Severe anterograde amnesia (cannot form new memories, does not recognise doctor)
• Retrograde amnesia (gap since approximately 2015)
• Confabulation (fabricated "fishing trip", plausible, fluent, believed by patient)
• Remote memory intact (childhood, family names, occupational knowledge)
• Alert and conversational, NOT demented in the global sense

Distinction from dementia:

• Dementia = global cognitive decline (multiple domains, attention, language, executive, memory, praxis)
• Korsakoff = SELECTIVE, anterograde memory grossly impaired; other domains relatively preserved
• Korsakoff patient can hold a normal conversation; demented patient cannot
• Korsakoff has profound amnesia with reasonable social facade

Three core cognitive features:

Confabulation, is it lying?

No. Confabulation is unintentional and unconscious. The patient genuinely believes the fabricated account. It arises because the memory system attempts to construct coherent narratives without access to accurate recent episodic memories. The patient has no awareness that the account is incorrect (anosognosia is also present, lack of insight into memory deficit). This distinguishes it from malingering.

Prognosis:

• 20–25% recover fully with sustained thiamine and alcohol abstinence
• 50% partial improvement (residual anterograde amnesia)
• 25% permanent, irreversible amnesia (mammillary body/thalamic damage too extensive)

Treatment:

• High-dose thiamine replacement (continue for months)
• Abstinence from alcohol, address alcohol dependence (OAMT, psychosocial)
• Reality orientation therapy (limited benefit for amnesia but helps adjustment)
• Occupational therapy for functional compensation
• Caregiver support and education
• Social support, cannot live independently if severe residual amnesia

Key Teaching Points:

• Wernicke's is acute and reversible; Korsakoff is chronic and largely irreversible, prevention (early thiamine) is everything
• The "temporal gradient" of retrograde amnesia: recent past is worse than remote (losing 2020–2023 more than losing 1990)
• Confabulation is not a character defect, it is a neurological symptom of a damaged memory system
• Thiamine BEFORE glucose, critical rule for any at-risk patient presenting to any emergency setting

VIGNETTE 05: The Young Man with Personality Change

Presentation:

Arjun, a 24-year-old engineering student, is brought by his parents who are concerned about a personality change over the past 18 months. He was previously described as responsible, academically bright, and even-tempered. He now shows poor impulse control, makes crude remarks in public, has dropped out of college, and spends hours rearranging objects on his desk.

He was initially seen by a psychiatrist who diagnosed schizophrenia and started risperidone 2 mg/day, with minimal improvement. Over the following months he developed a coarse tremor of both hands (worse with posture/intention), slurred speech, and difficulty swallowing. His LFTs were checked and found to be mildly elevated (ALT 78 U/L, AST 65 U/L).

On slit-lamp examination: Golden-brown deposits at the periphery of the cornea in Descemet's membrane, bilaterally.

Questions:

1. What is the diagnosis? What was the clinical trap?
2. What is the significance of the slit-lamp finding?
3. What investigations confirm the diagnosis?
4. Outline treatment.
5. What would happen if copper chelation is started without stopping risperidone?

Diagnosis: Wilson's Disease (Hepatolenticular Degeneration) with Neuropsychiatric Presentation

Clinical trap: Personality change + apparent psychosis in a young person → misdiagnosed as schizophrenia. Antipsychotics started without investigating cause. This is the cardinal diagnostic error in Wilson's disease.

Slit-lamp finding: Kayser-Fleischer (KF) rings, golden-brown copper deposits in Descemet's membrane of the cornea, at the periphery. Present in >99% of neurological Wilson's disease. KF rings are pathognomonic when found alongside neuropsychiatric or hepatic features.

Investigations:

Treatment:

• Acute chelation: D-penicillamine (penicillin derivative, chelates copper; SE: rash, nephrotoxicity, worsening neurological symptoms initially)
• Alternative chelation: Trientine (fewer side effects; preferred if neurological Wilson's)
• Maintenance: Zinc salts (block intestinal copper absorption; SE minimal)
• Liver transplant: Curative for hepatic disease; improves neurological disease; indicated in hepatic failure
• Dietary: Avoid copper-rich foods (shellfish, liver, nuts, chocolate)
• Stop risperidone, psychiatric symptoms should improve with copper chelation

Risperidone + chelation:

• D-penicillamine can initially worsen neurological symptoms (transient worsening in 20–50%, copper redistribution)
• Risperidone's EPS potential would compound this worsening
• Risperidone does not address the cause
• The psychiatric symptoms in Wilson's disease often improve substantially with copper chelation alone, antipsychotics may become unnecessary

Key Teaching Points:

• Wilson's disease is the great imitator in psychiatry, personality change, depression, OCD-like symptoms, psychosis in patients <40 years
• KF rings on slit-lamp in any young person with unexplained psychiatric + movement symptoms = Wilson's until proven otherwise
• Ceruloplasmin is the initial screen; 24h urine copper is the functional measure; liver biopsy is gold standard
• Never start antipsychotics in a young person without excluding Wilson's when movement disorder is also present

VIGNETTE 06: The Clever Conspiracy

Presentation:

Rajesh, a 44-year-old HIV-positive lorry driver diagnosed 7 years ago, attends for his 6-monthly review. He is on tenofovir/lamivudine/dolutegravir (switched from efavirenz 1 year ago). Viral load is undetectable, CD4 count 520 cells/μL.

His wife accompanies him and discloses privately that he has stopped his medication 3 times in the past 4 months. When asked, Rajesh says he doesn't want to take medicine every day, that the tablets make him feel like a patient, that his employer will "find out" if he is seen at a clinic, and that his neighbour recently died of AIDS despite taking medicine, so "what's the point."

PHQ-9 score: 14 (moderate depression). He endorses low mood, anhedonia, poor sleep, hopelessness, and poor concentration for the past 3 months. He denies suicidal ideation.

Questions:

1. What are the barriers to ART adherence in this vignette?
2. What is the relationship between his depression and non-adherence?
3. How would you manage the depression in the context of HIV and dolutegravir therapy?
4. What broader interventions improve adherence in this scenario?

Diagnosis: Moderate Depression (PHQ-9 = 14) with Multiple Adherence Barriers in HIV

Barriers to adherence:

Depression-adherence bidirectional relationship:

• Untreated depression: OR 3.4 for ART non-adherence (meta-analysis)
• Non-adherence leads to viral rebound → CD4 decline → increased biological depressogenic burden (viral proteins, cytokines)
• Poor adherence → HIV progression → hopelessness → deeper depression
• Breaking this cycle requires treating depression as a medical priority, not a secondary concern

Management of depression:

• Drug choice: Sertraline or escitalopram, minimal CYP interactions with dolutegravir (INSTI) regimen
• Note: Dolutegravir has fewer drug interactions than efavirenz; SSRIs generally safe
• CBT (adapted) and Interpersonal Therapy (IPT), both have evidence in HIV depression
• Combined pharmacotherapy + psychotherapy > either alone
• Address hopelessness as a cognitive distortion (CBT frame): Challenge catastrophic belief ("medicine didn't work for my neighbour")
• PHQ-9 monitoring at 4, 8, 12 weeks

Broader adherence interventions:

• Counselling: Motivational interviewing for ambivalence; psychoeducation about U=U (Undetectable=Untransmittable)
• Simplify regimen: Already on once-daily FDC (tenofovir/lamivudine/dolutegravir), optimal
• Practical aids: Phone alarm reminders, weekly pill organiser
• Disclosure support: Explore fear of employer; occupational rights counselling (HIV confidentiality)
• Peer support: Connect with HIV support group, normalises experience
• Long-acting injectable ART (if available): Cabotegravir + rilpivirine monthly IM, removes daily pill burden entirely
• Assess family support: Wife is engaged, involve her constructively

Key Teaching Points:

• Adherence is never a willpower problem alone, it is multi-determined (biological, psychological, social)
• Treating depression in HIV is a direct HIV management intervention, not a psychiatric add-on
• U=U (Undetectable = Untransmittable) is a powerful counselling tool for motivation and stigma reduction
• Stigma-driven non-adherence is common in occupations with high social visibility (lorry drivers, healthcare workers, teachers)

VIGNETTE 07: The Choreic College Student

Presentation:

Meghna, a 19-year-old first-year MBBS student, is referred by neurology. She presented 3 weeks ago with involuntary jerking movements of her arms and face, which started suddenly after a sore throat 6 weeks prior. The movements are described as flowing, unpredictable, non-repetitive, and worse with stress.

On psychiatric assessment: She is noted to have significant emotional lability, crying without provocation, then laughing inappropriately. Her mother reports she has become obsessively concerned about cleanliness (washing hands 30–40 times daily) and is anxious about "contaminating" her family. These OCD symptoms began simultaneously with the movements.

Past medical history: Two prior episodes of tonsillitis treated with amoxicillin.

Investigations:

• ASO titre: 480 IU/mL (elevated; normal <200)
• Anti-DNase B: Elevated
• Throat culture: Group A beta-haemolytic Streptococcus
• ECG: Normal (no PR prolongation, no carditis signs)
• MRI brain: Normal
• CBC and metabolic panel: Normal
• ANA, anti-dsDNA: Negative (SLE excluded)

Questions:

1. What is the diagnosis?
2. What is the mechanism linking streptococcal infection to psychiatric symptoms?
3. How does this presentation differ from OCD due to other causes?
4. Outline management.

Diagnosis: Sydenham's Chorea (with Psychiatric Manifestations, OCD and Emotional Lability)

Reasoning:

• Young patient post-streptococcal infection (elevated ASO titre, positive culture)
• Chorea with abrupt onset
• Associated psychiatric features: OCD-like symptoms and emotional lability
• MRI normal (not structural cause)
• SLE excluded (negative ANA, anti-dsDNA)
• This is part of Acute Rheumatic Fever (Jones criteria, chorea is a major criterion)

Mechanism, Molecular Mimicry:

• Group A streptococcal antigens cross-react with basal ganglia neuronal antigens (specifically, antibodies against streptococcal M protein cross-react with lysoganglioside epitopes on striatal neurons)
• Antibody-mediated neuronal dysfunction in caudate and putamen
• Basal ganglia and frontostriatal circuit disruption → chorea (motor) + OCD/repetitive behaviours (cognitive-behavioural) + emotional lability
• This is the same mechanism proposed for PANDAS (Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections), a related entity

Distinction from primary OCD:

Management:

Key Teaching Points:

• Sydenham's chorea = psychiatric + motor together; the OCD is not incidental, it is part of the same autoimmune process
• Molecular mimicry is the exam mechanism: Strep antibodies → cross-react with basal ganglia → frontostriatal circuit dysfunction → OCD + chorea
• Penicillin prophylaxis is mandatory, the single most important long-term intervention
• PANDAS is the related paediatric concept, episodic OCD/tics temporally related to streptococcal infections

VIGNETTE 08: The Sleepless Widower

Presentation:

Krishnamurthy, a 71-year-old retired schoolteacher and widower, presents with a 4-month history of deteriorating sleep. His daughter, who lives with him, reports that he talks, shouts, and thrashes about in bed, once falling out of bed and injuring his shoulder. He has vivid dreams, often of being chased, and appears to be "acting them out." He is distressed about this and has started sleeping on a mattress on the floor.

He also mentions that over the past 2 years, he has noticed his sense of smell is not as good as it used to be, and he has been constipated. Three months ago, he was noted by his GP to have mild resting tremor in his right hand.

On examination: Mild resting tremor right hand, subtle cogwheel rigidity right arm, gait mildly reduced arm swing on right. MoCA: 26/30 (loses 2 marks on visuospatial, 1 on delayed recall, 1 on fluency).

Polysomnography: Absence of normal REM atonia; complex movements correlating with dream content during REM sleep, confirms RBD.

Questions:

1. What is the sleep disorder? What is its clinical and prognostic significance?
2. What is the Braak staging concept and where does this patient sit?
3. What other early features of neurodegeneration are present in this vignette?
4. How would you counsel this patient and manage his sleep disorder?

Diagnosis: REM Sleep Behaviour Disorder (RBD) in the context of emerging Parkinson's Disease

RBD, Clinical and Prognostic Significance:

• In RBD, normal REM sleep atonia is absent → skeletal muscles remain active → patient acts out dream content (punching, kicking, shouting, falling)
• Prodromal marker of synucleinopathy: RBD is now recognised as one of the earliest and most specific prodromal markers of Parkinson's disease (and DLB and MSA)
• Longitudinal studies show: 80–90% of idiopathic RBD patients will develop a defined synucleinopathy within 10–14 years
• In this patient, he already has tremor and cogwheel rigidity, he has crossed from prodromal to early PD

Braak Staging:

• Braak et al. mapped the ascending spread of alpha-synuclein pathology in PD:
• Stages 1–2 (medulla, olfactory bulb): Anosmia, constipation, RBD, non-motor, preclinical
• Stages 3–4 (substantia nigra pars compacta): Motor symptoms emerge (tremor, rigidity, bradykinesia)
• Stages 5–6 (neocortex): Cognitive and psychiatric symptoms (dementia, psychosis)
• This patient has: Anosmia (Stage 1–2), constipation (Stage 1–2), RBD (Stage 1–2), and now tremor/rigidity (Stage 3–4)
• He is at Braak Stage 3–4 clinically, motor symptoms have just emerged

Other prodromal features present:

1. Hyposmia (anosmia), one of earliest PD prodromal markers; olfactory bulb involvement (Braak Stage 1)
2. Constipation, autonomic dysfunction; enteric nervous system Lewy pathology (Braak Stage 1–2)
3. RBD, loss of REM atonia (Braak Stage 1–2; locus coeruleus + pedunculopontine nucleus)
4. Cognitive changes on MoCA, visuospatial and fluency (Braak Stage 3–4 or early cortical involvement)

Counselling and Management:

Key Teaching Points:

• RBD is a prodromal biomarker, identifying it gives a window to monitor and potentially intervene before severe PD develops
• The triad of anosmia + constipation + RBD = very high predictive value for synucleinopathy
• Braak staging explains why psychiatric symptoms can appear long before or long after motor symptoms, depends on which circuits are involved
• Clonazepam + melatonin for RBD; avoid other sedating agents that suppress REM (benzodiazepines broadly suppress REM)

VIGNETTE 09: The Brilliant Confused

Presentation:

Sujata, a 35-year-old software engineer with known SLE (diagnosed 6 years ago, on hydroxychloroquine and low-dose prednisolone 7.5 mg/day), is admitted with a 3-day history of acute confusion, visual hallucinations (seeing "small children in the room"), and aggressive behaviour towards her husband.

Her prednisolone was increased to 60 mg/day by her rheumatologist 10 days ago following a flare (arthritis, pleuritis).

On examination: Alert but confused and disoriented in time and place. Responds to visual hallucinations. Blood pressure 156/98. Temperature 37.4°C. No meningism. Skin: butterfly rash present.

Investigations:

• CBC: Haemoglobin 9.8 g/dL, WBC 3200/mm3 (lymphopenia), platelets 98,000/mm3
• ANA: Positive (1:640)
• Anti-dsDNA: Markedly elevated (1:1280; previously 1:160)
• Complement: C3 low, C4 low
• CSF: 4 cells/mm3, protein 38 mg/dL, glucose normal; no organisms; ANA and anti-dsDNA sent from CSF
• MRI brain: Small T2/FLAIR hyperintensities in periventricular white matter; no cortical ribboning; no mass lesion
• EEG: Diffuse slowing, no epileptiform discharges

Questions:

1. What are the two competing diagnoses and how do you distinguish them?
2. What serological findings support NPSLE?
3. How does the rheumatology team's recent decision affect the picture?
4. How would you manage?

Competing Diagnoses:

1. NPSLE (Neuropsychiatric SLE, acute confusional state with psychosis)
2. Steroid-induced psychosis (high-dose prednisolone 60 mg/day)

Distinguishing features:

In this case:

• Anti-dsDNA markedly elevated (4× increase from baseline)
• Complement low (active SLE consumption)
• Lymphopenia, thrombocytopenia (active SLE features)
• White matter lesions on MRI (consistent with NPSLE)
• However: Prednisolone was increased to 60 mg/day 10 days ago, steroid psychosis is also possible
• Most likely: BOTH are contributing, active NPSLE requiring immunosuppression, PLUS steroid effects at 60 mg

Management:

Key Teaching Points:

• NPSLE vs steroid psychosis: the serology tells the story, elevated anti-dsDNA + low complement = active SLE = treat the disease, not just the symptom
• Both can coexist (this is the most realistic clinical scenario when a patient is on high-dose steroids for an active flare)
• The management paradox: You need steroids to treat NPSLE, but steroids may worsen the psychosis, solution is pulse dosing then taper with steroid-sparing agents
• Hydroxychloroquine has an independent CNS protective effect in SLE, never stop it during a flare

VIGNETTE 10: The Rapid Decline

Presentation:

Mohandas, a 67-year-old retired civil engineer with no prior psychiatric or neurological history, is referred urgently by neurology. Over the past 9 weeks he has developed rapidly progressive cognitive decline. His wife says he was entirely well 2 months ago, he was driving, managing the household finances, and playing chess regularly.

He now cannot recognise his grandchildren, is disoriented in his own home, cannot hold a conversation beyond a few seconds, and has developed jerking movements of his arms that are triggered by sudden sounds or touch. He also has poor coordination and an unsteady gait.

On examination: GCS 12/15. Disoriented in time, place, person. Stimulus-sensitive myoclonus. Cerebellar signs (dysdiadochokinesia, ataxic gait). Bilateral Babinski response. No fever. No meningism.

Investigations:

• CBC, metabolic panel: Normal
• Thyroid function: Normal
• Autoimmune screen (ANA, ANCA, anti-dsDNA): Negative
• CSF: 2 cells/mm3, protein 44 mg/dL, glucose normal; Gram stain negative; AFB negative
• CSF 14-3-3 protein: Positive
• MRI brain (DWI sequence): Cortical ribboning in right frontal and parietal cortex; bilateral caudate and putamen hyperintensity
• EEG: Biphasic periodic sharp wave complexes at approximately 1.5 Hz, generalised
• CSF RT-QuIC: Positive (reported 5 days later)

Questions:

1. What is the diagnosis? Justify using all investigation findings.
2. What is the significance of each investigation result?
3. What is the differential diagnosis and how is each excluded?
4. What is the prognosis? Is there any treatment?

Diagnosis: Sporadic Creutzfeldt-Jakob Disease (sCJD)

Justification:

Clinical features met (WHO Probable sCJD criteria):

• Rapidly progressive dementia (9 weeks, well within <2 years)
• 2 of 4 features: ✓ Myoclonus, ✓ cerebellar, ✓ pyramidal signs (bilateral Babinski)
• Supportive: EEG PSWC, positive 14-3-3
• Confirmatory: Positive RT-QuIC

Differential diagnosis exclusion:

Prognosis and Treatment:

• Invariably fatal, median survival from symptom onset is 4–6 months (median 4 months for sCJD)
• No disease-modifying treatment exists, no antiviral, antiprion drug has proven efficacy in human trials
• Quinacrine, pentosan polysulfate, doxycycline, all trialled, all failed in RCTs
• Management is palliative:
• Symptomatic treatment of myoclonus (clonazepam, valproate)
• Antipsychotics for agitation/psychosis (low dose)
• Palliative care team involvement early
• Family counselling and bereavement support
• Inform family: Not infectious via normal contact; blood and CSF are infectious materials
• Notifiable disease in most countries

Key Teaching Points:

• CJD is the fastest dementia, 9 weeks to this degree of impairment is virtually diagnostic in itself
• RT-QuIC is now the standard of care for CSF testing in suspected CJD, more specific than 14-3-3
• EEG PSWC differentiates sCJD from vCJD (vCJD does NOT show PSWC, use pulvinar sign for vCJD)
• DWI MRI is the most sensitive imaging modality, must specifically request DWI sequence
• Early palliative care involvement and family counselling are the most important clinical actions once diagnosis is confirmed

VIGNETTE 11: The Angry Choreographer

Presentation:

Dinesh, a 42-year-old dance teacher, is self-referred to psychiatry. He has been having increasing difficulty with his temper over the past 3 years, explosive outbursts at students and family members, which feel "out of character." He has also noticed that he drops objects, trips occasionally, and his handwriting has changed.

His father died in a mental institution at age 55 after "going mad and not being able to walk." His 38-year-old brother was recently diagnosed with Huntington's disease.

On examination: Alert, oriented, cooperative but tangential. Mild choreiform movements of fingers and mouth (subtle, present on observation). MMSE 27/30 (loses marks on serial 7s and drawing). Reflexes normal. Speech slightly dysarthric.

He says he does not want genetic testing because "I can't deal with knowing."

Questions:

1. What is the clinical diagnosis and how is it established?
2. He refuses genetic testing. Is his right to refuse valid? How do you handle this ethically?
3. His wife asks you privately to tell her his result "if you do test him." How do you respond?
4. He has a 16-year-old son. Should the son be tested?
5. What is the psychiatric management for this stage of HD?

Diagnosis: Huntington's Disease (clinically probable, pending genetic confirmation)

Clinical basis:

• Age 42, male, within typical HD onset range
• Family history: Father (probable HD, psychiatric + motor decline), brother (confirmed HD)
• Autosomal dominant, 50% risk to Dinesh; brother's confirmed diagnosis makes Dinesh's risk 50% from first principles
• Clinical signs: Choreiform movements (subtle, early), dysarthria, personality change/irritability (often first psychiatric symptom), cognitive decline on MMSE (executive domain)
• Genetic confirmation: CAG repeat analysis on HTT gene, but patient is refusing

Ethical management of refusal to test:

• His refusal is COMPLETELY VALID, the right NOT to know is as fundamental as the right to know (HDSA guidelines, genetic testing ethics literature)
• The psychiatrist's role: Respect autonomy; explore his fears (is it fear of a positive result? Fear of what he'll do with the information? Financial concerns?); psychoeducation; leave the door open
• Do NOT coerce testing
• Even without genetic confirmation, clinical diagnosis can be made and management initiated
• Genetic testing adds certainty and facilitates family planning but is not mandatory for management

Wife's request for private disclosure:

• Cannot be done, Dinesh's genetic result is his private medical information
• His wife's desire to know is understandable but does not override his right to confidentiality
• Response to wife: "I understand your concern and it must be very difficult. However, I am not able to share any medical information about your husband without his consent. If he changes his mind about testing or sharing, he can choose to involve you. I am happy to support both of you through this."
• If Dinesh tests and gets a positive result and consents to disclosure to wife, then share

16-year-old son, should he be tested?

• No, not recommended
• Reasons:
• Cannot give informed consent, a minor cannot fully appreciate the lifelong implications of a positive result
• No medical benefit, there is no treatment that would change management in a healthy adolescent
• Right not to know must be preserved until adulthood (at 18, he can make an informed autonomous choice)
• Psychological harm from a positive result in adolescence (identity formation, educational decisions, depression, suicidality) may be significant with no counterbalancing benefit
• Exception: If the son has symptoms suggestive of juvenile HD (rigidity, cognitive decline, school failure), then symptomatic testing is warranted

Psychiatric management of early HD:

• Irritability (presenting complaint): SSRIs (sertraline 50–100 mg), first-line; valproate if severe
• Depression screening: PHQ-9; start SSRI prophylactically given high suicide risk
• Suicide risk assessment: First post-diagnosis period is highest risk, establish safety plan
• Cognitive changes: Occupational assessment; teaching adaptations (cognitive strategies)
• Family therapy: Wife, son, psychoeducation about HD, genetic implications, support resources
• Genetic counselling referral: For wife and son to understand their situation
• Chorea: Not yet severe enough to treat; monitor; tetrabenazine if becomes functionally limiting
• Support groups: HD Association of India or international HDSA resources

Key Teaching Points:

• The right not to know genetic information is a fundamental ethical principle, as valid as the right to know
• Confidentiality cannot be broken for a family member who wants results, not even a spouse
• Children: Predictive testing not recommended, preserve their right to autonomous decision-making at adulthood
• HD has two clinical triggers for suicide: immediately after diagnosis and when motor symptoms begin (loss of independence), monitor both

VIGNETTE 12: The Man Who Forgot to Be Sad

Presentation:

Subramanian, a 74-year-old widower with a 9-year history of Parkinson's disease, attends with his son. He is on levodopa/carbidopa 250/25 mg QID, entacapone 200 mg QID, and rivastigmine patch 9.6 mg/24h (started 18 months ago for PD dementia).

His son is worried because "Appa doesn't do anything anymore." He sits all day, has stopped watching cricket (which he loved), stopped calling friends, and eats only when reminded. When asked, he says he feels "fine" and is "not sad." He denies anhedonia when asked directly. However, he will not initiate any activity spontaneously.

His son had also noted that last week, he started crying suddenly in the middle of dinner for about 2 minutes, then stopped abruptly and resumed eating normally. "It was like he flipped a switch," the son says.

On examination: MMSE 18/30 (consistent with PD dementia). Bradykinesia and rigidity present. Hypomimic face. Flat affect on examination. No expressed sadness or dysphoria. No endorsement of hopelessness or suicidality.

Questions:

1. Name the two distinct neuropsychiatric phenomena in this vignette and distinguish them.
2. What is the key clinical question that separates apathy from depression in this case?
3. What does the dinner episode represent and how is it treated?
4. What is the management for apathy in PD dementia?

Diagnosis:

1. Apathy (reduced motivation, no negative affect, no distress)
2. Pseudobulbar Affect / PBA (involuntary crying episode, incongruent with emotional state)

Distinguishing apathy from depression:

Key clinical question: "Does this patient feel bad about not doing things, or do they simply not care either way?"

• Depressed patient: "I want to watch cricket but I can't bring myself to, I feel terrible about it"
• Apathetic patient: "Cricket? I don't feel like it. I don't know. It doesn't bother me."

The dinner episode, Pseudobulbar Affect:

• Abrupt onset, sudden offset, 2-minute episode of crying
• Not triggered by sad thought or emotion (mid-dinner, normal context)
• Incongruent with mood state (resumes eating normally after)
• Son's description ("like flipping a switch") is classic
• Mechanism: PD cortical Lewy body pathology disrupts corticobulbar tracts → loss of prefrontal inhibition of brainstem emotional expression circuits
• Treatment: SSRIs (citalopram or fluoxetine), rapid response, often within days; dextromethorphan/quinidine (Nuedexta), FDA-approved for PBA but not available in India

Management of apathy in PD dementia:

• Optimise dopaminergic therapy, dopamine is the neurotransmitter of motivation; motor optimisation helps apathy
• Rivastigmine (already on), cholinesterase inhibitor has some evidence for apathy in PDD/DLB
• Methylphenidate, small trials show benefit for apathy in PD; off-label
• Structured daily schedule, caregiver-assisted; routine reduces the barrier of initiation
• Physical exercise, externally motivated; improves mood and motivation in PD
• Occupational therapy, goal-setting, meaningful activity identification
• No strong evidence for SSRIs for apathy in PD (SSRIs treat depression, not pure apathy; may even slightly worsen apathy in some by reducing dopamine turnover)
• Key distinction: Do NOT give antidepressants for apathy without depression, they are different disorders with different neurobiology

Key Teaching Points:

• Apathy = Depression: The most clinically important distinction in PD psychiatry. Misdiagnosing apathy as depression and starting SSRIs will not help and wastes time
• PBA is common in PD dementia, the "flipping switch" description from a carer is almost diagnostic
• PBA responds to SSRIs rapidly (days), unlike antidepressant effects on mood (weeks)
• Rivastigmine treats cognition AND has a small but real benefit for apathy in PDD, it is doing double duty in this patient