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Differentiating Neurological-Organic Psychiatric Features vs. Primary Psychiatric Disorders

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1. The Core Concept: "Organic" Red Flags

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2. Disease-by-Disease Breakdown

A. Autoimmune Encephalitis (e.g., Anti-NMDA Receptor Encephalitis)

The disorder has a characteristic pattern of symptom progression that often includes a prodrome resembling a viral process, followed in a few days by the onset of severe psychiatric symptoms, sleep dysfunction (usually insomnia), reduced verbal output, memory loss, seizures, decreased level of consciousness, abnormal movements (orofacial, limb, and trunk dyskinesias, dystonic postures), autonomic instability, and frequent hypoventilation.

• LGI1 — faciobrachial dystonic seizures + amnesia, hyponatremia
• CASPR2 — Morvan syndrome, neuromyotonia + psychiatric + autonomic
• GABA-B — prominent seizures + psychosis
• AMPA-R — relapsing psychosis, limbic involvement
• VGKC complex — confusion, hyponatremia, sleep disorder

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B. Paraneoplastic Syndromes

• Subacute onset (weeks to a few months)
• Associated occult malignancy (lung, breast, ovarian, thymoma, testicular)
• Limbic encephalitis pattern: amnesia + psychiatric symptoms + seizures
• Associated systemic symptoms: weight loss, night sweats, fatigue
• Classic antibody-tumor pairings:

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C. Infectious Encephalitis

• Psychiatric features (personality change, bizarre behavior) + temporal lobe involvement
• Fever (though may be absent early), headache, seizures
• MRI: hemorrhagic changes in medial temporal lobes and orbitofrontal cortex — characteristic and not seen in schizophrenia
• CSF: lymphocytic pleocytosis, elevated protein, PCR positive for HSV
• EEG: temporal periodic lateralized epileptiform discharges (PLEDs)
• Urgency: empirical acyclovir must not be delayed pending confirmation

• Any psychiatric presentation in a sexually active person, especially with dementia + personality change
• Argyll Robertson pupils (accommodate but don't react to light) — pathognomonic
• RPR/VDRL + FTA-ABS, CSF VDRL

• AIDS dementia complex, opportunistic CNS infections (Toxoplasma, Cryptococcus, CMV)
• CD4 count context critical

• Rapidly progressive dementia + psychiatric features + myoclonus
• MRI DWI: cortical ribboning + basal ganglia signal — highly characteristic
• EEG: periodic sharp wave complexes
• CSF 14-3-3 protein

Cases were reported where patients carried the diagnosis of schizophrenia for years prior to their WD diagnosis.

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D. Seizure-Related Psychiatric Syndromes

• Confirmed epilepsy on EEG (though interictal EEG can be normal — requires prolonged monitoring)
• Temporal relationship to seizure clusters (for ictal/postictal)
• Often affectively warm (intact affect) despite psychotic content — in contrast to the flat/blunted affect of schizophrenia
• Visual hallucinations > auditory (opposite pattern in schizophrenia)
• Absence of negative symptoms (alogia, avolition, anhedonia)

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3. Systematic Investigation Algorithm

Tier 1 — Always

• CBC, CMP (electrolytes, glucose, renal, hepatic)
• TFTs (thyroid — hypothyroid and hyperthyroid both cause psychiatric features)
• B12, folate, thiamine
• Urine drug screen + alcohol
• Urine toxicology (heavy metals if indicated)
• Syphilis serology (RPR + FTA-ABS)
• HIV
• Urinalysis (UTI-precipitated delirium, especially in elderly)

Tier 2 — When neurological features present

• MRI brain with contrast + FLAIR (structural lesion, temporal lobe signal change, demyelination)
• EEG (seizure activity, encephalopathic slowing, temporal foci)
• CSF analysis (LP): opening pressure, cell count, protein, glucose, Gram stain + culture, HSV/VZV/CMV/EBV PCR, oligoclonal bands, IgG index, cytology

Tier 3 — Directed by clinical picture

• Autoimmune antibody panel: anti-NMDA-R, LGI1, CASPR2, AMPA-R, GABA-B, VGKC (serum AND CSF — sensitivity is higher in CSF for some)
• Paraneoplastic panel: anti-Hu, Yo, Ri, Ma2, CV2, amphiphysin
• CT chest/abdomen/pelvis or PET (occult malignancy)
• Ceruloplasmin, 24hr urine copper, slit-lamp exam (Wilson's)
• Cortisol, ACTH (Addison's, Cushing's)
• ANA, ANCA, complement (systemic vasculitis, SLE with CNS involvement)
• Porphyria screen (urine porphyrins)

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4. Clinical Heuristic: Features That Favor Primary Psychiatric Disorder

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5. Summary Comparison Table

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Key Clinical Pearls

1. Anti-NMDA encephalitis is the great mimicker — it can look like first-episode schizophrenia, especially in young women. The presence of orofacial dyskinesias, autonomic instability, or rapid cognitive decline should break the mimic.
2. Postictal psychosis has a lucid interval — the patient is calm for 12–72 hours after seizures, then becomes psychotic. This temporal pattern is highly distinctive.
3. Wilson's disease must be excluded in any psychiatric presentation under age 40 — it is treatable and reversible if caught early.
4. Cortical ribboning on DWI-MRI is virtually pathognomonic of CJD in the right clinical context.
5. Negative symptoms (alogia, avolition, flat affect) are rare in organic psychoses and, when prominent, strongly favor schizophrenia.
6. Test CSF, not just serum, for autoimmune antibodies — sensitivity for NMDA-R and some others is significantly higher in CSF.
7. A patient with known cancer who develops psychiatric features should be assumed paraneoplastic until proven otherwise.

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Psychiatric Symptoms in TBM on ATT (2 Months) — Etiological Framework

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Causes to Consider — Categorized

1. Disease-Related: TBM Itself (Direct CNS Injury)

Key point: Hydrocephalus and vasculitis are the two most common causes of neurological deterioration in TBM patients who are already on treatment. Both can present primarily as psychiatric features.

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2. Drug-Related: ATT Neuropsychiatric Toxicity

Isoniazid (INH) — Most Important

• Acute psychosis (visual and auditory hallucinations, paranoid delusions)
• Euphoria, hypomania
• Depression
• Obsessive-compulsive features
• Memory impairment
• Seizures (which can then cause postictal psychosis)

Cycloserine — Highly Psychiatric

• Most neuropsychiatric of all TB drugs
• Can cause: psychosis, depression, suicidal ideation, anxiety, seizures, confusion
• Mechanism: NMDA receptor partial agonist + interferes with B6-dependent neurotransmitter synthesis
• If the patient is on a DR-TB regimen, cycloserine must be high on the differential

Ethionamide / Prothionamide

• Depression, personality change, psychosis (less common than cycloserine)
• Also depletes B6

Fluoroquinolones (Levofloxacin/Moxifloxacin)

• Used in TBM for CNS penetration
• Rare but documented: psychosis, delirium, anxiety, insomnia

Ethambutol

• Primarily optic neuritis — minimal psychiatric effects

Rifampicin

• Rarely causes psychiatric effects directly
• But induces CYP enzymes — may lower levels of psychiatric medications if co-prescribed

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3. Paradoxical Reaction (Immune Reconstitution Inflammatory Syndrome)

• Occurs in ~10–15% of TBM patients, typically within weeks to months of starting ATT
• Mechanism: restoration of immune response → worsening inflammation at existing lesions or development of new tuberculomas
• 2 months is exactly the right window for paradoxical reactions
• Can cause: increasing headache, new focal deficits, new seizures, worsening CSF, enlarging tuberculomas
• If a frontal or temporal tuberculoma enlarges → psychiatric features, personality change, psychosis
• Management: corticosteroids (if not already on them), continue ATT, neurosurgical evaluation if mass effect

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4. Metabolic / Systemic Complications

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5. Corticosteroid-Induced Psychiatric Features

• Dexamethasone is standard in TBM — typically given for 6–8 weeks then tapered
• Steroid psychosis is well recognized:
  • Usually within first 1–2 weeks of high-dose use
  • But can occur at any stage, including during taper (withdrawal-related)
  • Mania, euphoria, psychosis, depression, anxiety
  • At 2 months, the patient may be on a tapering dose — both too-rapid taper AND ongoing steroid use can trigger psychiatric features

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6. True Comorbid Primary Psychiatric Disorder

• Coincidental first episode of schizophrenia or bipolar disorder (TBM prevalence is highest in 15–35 year age group, overlapping with schizophrenia onset)
• However, this is a diagnosis of exclusion — only after ruling out all the above

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Practical Approach: What To Do

Step 1 — Immediate Bedside Assessment

• Full neurological exam: GCS, focal signs, papilledema (raised ICP/hydrocephalus)?
• Vital signs: fever (paradoxical reaction, new superinfection)?
• Mental status: confusion + psychiatric features → delirium first?

Step 2 — Urgent Investigations

Step 3 — Targeted Management Based on Cause

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Summary Decision Tree

TBM patient on ATT × 2 months → new psychiatric symptoms
                    │
     ┌──────────────┼───────────────┐
     ▼              ▼               ▼
 Drug toxicity   Disease         Systemic
 (INH/Cyclo-     complication    complication
  serine/         │               │
  Steroids)       ├─ Hydrocephalus (MRI)
     │             ├─ Vasculitis/infarct (MRI/DWI)
     │             ├─ Paradoxical tuberculoma
     │             └─ Limbic/cortical TBM
     │                              │
     │                              └─ Hyponatremia (SIADH)
     │                                 ATT hepatotoxicity
     │                                 Adrenal insufficiency
     ▼
Check: Is patient on cycloserine? → High priority
Check: Is pyridoxine prescribed? → If not, INH toxicity likely
Check: Steroid dose/taper stage? → Steroid psychosis

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Bottom Line

1. Never assume it is a primary psychiatric disorder without full exclusion
2. INH-related pyridoxine deficiency is common, preventable, and easily treated — check if B6 supplementation was prescribed
3. Hydrocephalus is the most dangerous structural cause and requires urgent MRI
4. Paradoxical reaction at 2 months is biologically plausible and radiologically identifiable
5. Hyponatremia (SIADH) from TBM itself is frequently missed and easily corrected
6. If on a DR-TB regimen with cycloserine, this drug alone can cause full psychotic episodes