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ANTIBODY MEDIATED


ANTI-NMDA RECEPTOR ENCEPHALITIS

Antibodies are directed against the NR1 subunit of the NMDA receptor. Clinical manifestations typically include:

  • A prodrome, this may last several weeks, symptoms include fever, headache, nausea, vomiting and diarrhea
  • A symptomatic phase, symptoms may include all of the following:
    • Psychiatric and behavioral symptoms: anxiety, bizarre behavior, delirium, paranoia
    • Insomnia or hypersomnia
    • Altered level of consciousness
    • Seizures (focal or generalized)
    • Movement disorders: oral-motor dyskinesias, choreiform movements
    • Hypoventilation
    • Autonomic instability: incontinence, tachycardia, hypertension, hyperthermia

CSF may show lymptocytic pleocytosis, elevated protein, positive oligoclonal bands. MRI is abnormal in a third of cases with cortical/subcortical hyperintensities commonly seen. EEG usually shows diffuse slowing and may show extreme delta brush pattern. Diagnosis is supported by identification of NMDA receptor antibody in CSF (serum may be negative). In women the risk of ovarian teratoma is high and this should be excluded.

VOLTAGE-GATED POTASSIUM CHANNEL ANTIBODY (LGI1 or CASPR2)

Antibodies directed against the voltage gated potassium channels bind to other proteins including LGI1 (leucine-rich, glioma-inactivated 1 protein) and CASPR2 (contactin-associated protein 2) resulting in a complex antibody. These antibodies cause limbic encephalitis with the following common features:

  • Short term memory loss
  • Intractable focal seizures with a high frequency, these commonly have temporal lobe features; however olfactory aura and pilomotor features (resulting in shivering phenomena) may be distinctive
  • Faciobrachial dystonic seizures (brief episodes of unilateral facial grimace and arm posturing) - these are characteristic of antibody to LGI1
  • Hyponatremia
  • Dysautonomia
  • Sleep disturbance
  • Psychiatric symptoms

CSF findings are usually normal. Neuroimaging may be normal but often shows mesial temporal T2 hyperintensity which is usually asymmetric and does not enhance. EEG often shows frontotemporal or generalized slowing and focal temporal epileptiform discharges. Diagnosis is supported by identification of voltage gated potassium channel antibody in serum (or anti-LGI1 or anti-CASPR2), antibody may not be present in CSF.

GAD65 ANTIBODY

Low titers of GAD65 are commonly seen as a marker of thyrogastric autoimmunity and are not concerning for neurological disease. Very high titers (>20 nmol/l in serum) can be associated with variable neurological symptoms including limbic encephalitis. Diagnosis is supported by identification of GAD65 antibody in serum.

GABA-B RECEPTOR ANTIBODY

GABA-B receptor antibodies may present with limbic encephalitis and are most commonly found in adults with small cell lung cancer. Diagnosis is supported by identification of GABA-B receptor antibody in serum.

AMPA RECEPTOR ANTIBODY

AMPA receptor antibodies may present with limbic encephalitis and are most commonly found in older patients in association with cancers of the thymus, breast or lung. Diagnosis is supported by identification of AMPA receptor antibody in serum. Given the risk of cancer, this should be excluded.

STEROID-RESPONSIVE ENCEPHALOPATHY ASSOCIATED WITH THYROID DISEASE

Anti-TPO antibody, present in this disorder, is common in the population. The following criteria are therefore proposed for the clinical diagnosis of steroid-responsive encephalopathy associated with thyroid disease:

  • Encephalopathy with cognitive impairment, neuropsychiatric features, seizures and/or focal neurological deficits
  • Euthyroid or mildly hypothyroid (requires T4 and TSH evaluation)
  • No evidence of toxic, metabolic, infectious or neoplastic cause
  • No other specific anti-neuronal antibody implicated
  • No findings on MRI to suggest vascular, neoplastic or other structural etiology
  • Complete or near complete response to steroids

Diagnosis is supported by identification of anti-TPO receptor antibody in serum and the exclusion of other etiologies (requiring full testing of serum and CSF, including searches for other anti-neuronal antibodies).

CELIAC DISEASE, EPILEPSY AND CEREBRAL CALCIFICATION SYNDROME

An association between epilepsy and celiac disease has been debated however has not been convincingly established in more careful studies. Celiac disease, epilepsy and occipital calcifications is a rare condition with the following characteristics:

  • Mean age at onset is 6 years
  • Bilateral cortical/subcortical parieto-occipital calcifications without brain atrophy
  • Focal seizures with elementary visual aura are common, these may evolve to a bilateral convulsion
  • Many cases respond to anti-seizure medications, however some require a gluten free diet for seizure control
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