Step 2 CK · Neurology

Paraneoplastic & Autoimmune Encephalitis Syndromes

Name: Paraneoplastic & Autoimmune Encephalitis Syndromes
Creator: Veli Bakalov, MD

Name the antibody, find the tumor, and treat before the results return

Neurology·Neurologic Complications of Systemic Disease·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Autoimmune encephalitis = subacute (<3 months) memory loss, psychiatric change, and seizures; cell-surface antibodies respond to immunotherapy, intracellular onconeural antibodies signal cancer and poor recovery.
Anti-NMDA receptor: young woman with psychosis, then seizures, orofacial dyskinesias, autonomic instability, and hypoventilation; MRI often normal; extreme delta brush on EEG.
Anti-NMDA receptor encephalitis → pelvic MRI or transvaginal ultrasound for ovarian teratoma and resect it; it can also follow HSV encephalitis by weeks.
Anti-LGI1: older man with faciobrachial dystonic seizures and hyponatremia; responds to immunotherapy better than to antiseizure drugs.
Anti-Hu = small cell lung cancer with sensory neuronopathy and encephalomyelitis; anti-Yo = ovarian/breast cancer with subacute cerebellar degeneration.
Anti-Ri = breast/lung cancer with opsoclonus-myoclonus; a child with opsoclonus-myoclonus needs a neuroblastoma search (urine HVA/VMA, imaging).
Anti-Ma2 = testicular germ cell tumor (limbic, hypothalamic, brainstem encephalitis); anti-amphiphysin (cancer) or anti-GAD65 (type 1 diabetes) = stiff-person syndrome.
Work-up: MRI mesial temporal FLAIR, CSF pleocytosis/oligoclonal bands, EEG, serum plus CSF antibodies, CT chest/abdomen/pelvis ± FDG-PET, pelvic or testicular ultrasound.
Treat: IV acyclovir until HSV excluded; tumor removal plus steroids, IVIG, or plasma exchange; rituximab or cyclophosphamide if no response in ~2 weeks.

Recognizing autoimmune encephalitis

Presentation. Autoimmune encephalitis evolves subacutely, over less than 3 months, with short-term memory loss, confusion, psychiatric change, and seizures. Suspect it when these accompany new focal signs, a CSF pleocytosis, or MRI evidence of encephalitis and infection has been reasonably excluded. Limbic encephalitis (amnesia, temporal-lobe seizures, and behavioral change) is the classic pattern.

Two antibody families. The target antigen predicts mechanism, cancer risk, and prognosis.

Cell-surface vs intracellular antibodies

Feature	Cell-surface / synaptic	Intracellular (onconeural)
Examples	NMDA receptor, LGI1, CASPR2, GABA-B, AMPA	Hu, Yo, Ri, Ma2, amphiphysin
Mechanism	Antibody is pathogenic: blocks or internalizes its target	Cytotoxic T cells destroy neurons; antibody is a marker
Cancer link	Variable (ovarian teratoma with NMDA receptor)	Strong (lung, breast, ovary, testis)
Outcome	Good with immunotherapy ± tumor removal	Poor; treating the tumor is the priority

Anti-NMDA receptor and anti-LGI1 encephalitis

Anti-NMDA receptor encephalitis. Most patients are young women or children. A viral-like prodrome (fever, headache) is followed by psychiatric symptoms (anxiety, insomnia, psychosis, catatonia) with memory and speech decline, then seizures and falling responsiveness, and finally orofacial dyskinesias and choreoathetosis, autonomic instability (arrhythmias, blood pressure swings, hyperthermia), and central hypoventilation requiring ICU care. MRI is often normal. EEG shows slowing and sometimes extreme delta brush (rhythmic delta with superimposed fast activity), a characteristic pattern.

Tumor and triggers. In adult women an ovarian teratoma containing NMDA receptor-bearing neural tissue is common, so image the pelvis with MRI or transvaginal ultrasound and resect any tumor; removal speeds recovery and lowers relapse risk. Tumors are rare in children and men. The syndrome can also follow HSV encephalitis by weeks, appearing as a "relapse" with new psychiatric symptoms or choreoathetosis and a negative HSV PCR; this needs immunotherapy, not more antiviral treatment.

CSF is more sensitive than serum for NMDA receptor antibodies: send both and never exclude the disease on a negative serum test. Antipsychotics are poorly tolerated and do not treat the cause.

Anti-LGI1 limbic encephalitis. Mostly men in their 60s develop amnesia, confusion, and seizures, often heralded by faciobrachial dystonic seizures: very brief, frequent jerks or posturing of one arm and the same side of the face. Hyponatremia from SIADH is common, CSF may be normal, and tumors are uncommon. The seizures respond better to immunotherapy than to antiseizure drugs, and early treatment prevents lasting amnesia.

Onconeural antibody syndromes

Antibody, tumor, and syndrome

Antibody	Main tumors	Syndrome
Anti-Hu (ANNA-1)	Small cell lung cancer	Sensory neuronopathy, encephalomyelitis, GI pseudo-obstruction
Anti-Yo (PCA-1)	Ovarian, breast, other gynecologic	Subacute cerebellar degeneration
Anti-Ri (ANNA-2)	Breast, lung	Opsoclonus-myoclonus, brainstem syndrome, jaw dystonia
Anti-Ma2 (Ta)	Testicular germ cell tumor	Limbic, hypothalamic, upper brainstem encephalitis
Anti-amphiphysin	Breast, small cell lung cancer	Stiff-person syndrome
Anti-GAD65	Usually none	Stiff-person syndrome, cerebellar ataxia; type 1 diabetes

Anti-Hu. Usually a smoker with small cell lung cancer: painful, asymmetric sensory neuronopathy of the dorsal root ganglia with sensory ataxia, pseudoathetosis, and areflexia, plus limbic, brainstem, cerebellar, or spinal encephalomyelitis and autonomic failure. Neurologic symptoms usually precede the cancer diagnosis.

Anti-Yo. Women develop severe truncal and limb ataxia, dysarthria, and nystagmus over weeks to months from Purkinje cell loss. MRI is initially normal, with atrophy later, and most patients stay disabled despite tumor treatment. Rapid cerebellar ataxia with a normal MRI in a middle-aged woman is paraneoplastic until proven otherwise: order mammography and pelvic imaging.

Anti-Ri and opsoclonus-myoclonus. Opsoclonus (chaotic, multidirectional saccades) with myoclonus, sometimes with jaw dystonia or laryngospasm. In a toddler, opsoclonus-myoclonus-ataxia signals neuroblastoma in about half: check urine HVA and VMA and image the chest and abdomen (± MIBG scan). Pediatric cases usually lack an identifiable antibody, often need ACTH or steroids, IVIG, or rituximab, and may leave lasting developmental problems.

Anti-Ma2. Young men with testicular germ cell tumors develop limbic seizures and amnesia, hypothalamic features (hypersomnolence, narcolepsy-cataplexy, hyperphagia, endocrine failure), and upper brainstem signs such as vertical gaze palsy. Testicular ultrasound is indicated even when the testes feel normal; removing a small tumor can stabilize the syndrome.

Stiff-person syndrome. Fluctuating axial and proximal-leg rigidity, lumbar hyperlordosis, and painful spasms triggered by noise, touch, startle, or emotion; EMG shows continuous motor unit activity in agonist and antagonist muscles. GAD65 makes GABA, so lost inhibition explains the stiffness. Anti-GAD65 disease accompanies type 1 diabetes, thyroiditis, and vitiligo, whereas anti-amphiphysin points to cancer. Treat with diazepam, baclofen, and IVIG.

Work-up

IV acyclovirStart at once and continue until the HSV PCR is negative; HSV is the key infectious mimic
MRI brainMesial temporal FLAIR hyperintensity in limbic encephalitis; often normal in NMDA receptor disease
Lumbar punctureLymphocytic pleocytosis, mildly raised protein, oligoclonal bands; may be normal
Antibody panelsSerum and CSF together
EEGSeizures, nonconvulsive status, slowing, extreme delta brush
Tumor searchCT chest, abdomen, and pelvis, then FDG-PET; pelvic MRI or transvaginal ultrasound, mammography or breast MRI, testicular ultrasound as the antibody suggests

If no tumor is found in a high-risk antibody syndrome, repeat the cancer search periodically: the neurologic syndrome often appears first.

Treatment and prognosis

First line. Remove the tumor and give IV methylprednisolone, IVIG, or plasma exchange, often combined. Start once infection is reasonably excluded, without waiting for antibody results. Supportive care covers seizures, dyskinesias, autonomic instability, and ventilation.

Second line and maintenance. With no improvement in about 2 weeks, add rituximab or cyclophosphamide. Maintenance options include a steroid taper, mycophenolate, azathioprine, or repeat rituximab. Multiple sclerosis drugs have no role.

Prognosis. Most anti-NMDA receptor patients recover substantially over months; relapses occur in a minority. Intracellular-antibody syndromes improve little because neurons are already lost, so early cancer treatment is the main lever.