How to evaluate the patient with unexplained encephalopathy, and a practical approach to diagnosing autoimmune encephalitis with an emphasis on anti-NMDA receptor encephalitis—with Dr. Casey Albin (@CaseyAlbin), neurologist and neurointensivist, assistant professor of Neurology and Neurosurgery at Emory, and part of the NeuroEmcrit team.
- Common causes of unexplained encephalopathy are:
- Metabolic/systemic problems (myxedema, hypercarbia, uremia, vitamin deficiency, etc), which are common, but often found on routine labs.
- Toxicologic exposures (drugs, heavy metals like Wilson’s, etc)
- Primary neurologic events. These differentiate into acute and subacute processes.
- In the altered patient found down with normal CT head and grossly normal labs, consider seizure and tox causes.
- Give thiamine indiscriminately and widely to patients with altered mental status; it is harmless and Wernicke-Korsakoff may fool you.
- Start with the history and meds. Simple intoxications like baclofen overdose can cause incredibly dense coma.
- Inquire as to recent history of behavioral changes, neurologic phenomena, illness, etc. Prolonged or subacute symptoms significantly narrow the differential of a neurologic cause.
- Always consider basilar artery stroke in the obtunded patient with a non-focal exam! Get a CTA early to evaluate the posterior circulation, as they may be a candidate for thrombolysis or thrombectomy.
- With an unexplained diagnosis suspected to be neurologic in nature, have a low threshold for obtaining MRI (generally with gadolinium), lumbar puncture, and EEG. The urgency and order of these may depend on clinical suspicion, other tests, and availability. A spot EEG to rule out status epilepticus, followed by either LP or MRI (whichever is available first) is often a good sequence.
- Have a relatively high threshold to start anti-epileptics for “seizure risk” or for vaguely epileptiform activity on EEG in the absence of true seizure, particularly if continued EEG monitoring (either continuous or frequent spot studies) are readily available. These drugs tend to remain prescribed for a long time, are not often discontinued by downstream providers, and can lead to future polypharmacy and lifestyle impacts.
- To unpack autoimmune causes, build a syndrome by considering the timeline and the affected areas (e.g. portions of the brain or spine involved on imaging).
- Creutzfeldt-Jakob disease should be suspected from the clinical history, or classic MRI findings such as cortical ribboning and “hockey sticks” in the basal ganglia. Without some specific suspicion, testing is usually not indicated.
- A normal brain MRI can occur in some autoimmune encephalitides. For instance, anti-NMDAR encephalitis can have absolutely normal MRIs, which can be a helpful differentiator from limbic encephalitis (the latter tending to have characteristic MRI findings).
- The Mayo Clinic and ARUP laboratories have a broad autoimmune encephalitis panel that can be sent for undifferentiated encephalitis; it tests for multiple antibodies and is updated periodically in response to new research. It is not particularly cheap, but with the large number of overlapping syndromes, when autoimmune causes are suspected it is generally a better idea than targeted testing in all but the most classic clinical pictures.
- Draw plenty of CSF for all these labs, at least 30 cc if possible. You don’t want to have to go back just because you thought of another test.
- Normal CSF protein increases with age. A good rule of thumb for pathological elevation is CSF protein that is greater than the patient’s age.
- With a sick patient and legitimate suspicion for an autoimmune cause responsive to immunomodulation, treat empirically. Your options are steroids (e.g. five days, 1000mg daily of methylprednisolone, then possible maintenance dosing depending on the diagnosis), plasma exchange (PLEX, usually 5 treatments, one every other day), or IV immunoglobulin (IVIG). Often you’ll combine pulse-dose steroids with one of the latter. Either PLEX or IVIG are a reasonable option, although some syndromes seem to respond better to PLEX. Either way , you’ll need to commit to doing this before autoimmune tests results (which takes around ten days), and generally continue treatment until you have your results, since clinical response in many syndromes may take weeks.
- If test results are negative, consider repeating some studies (e.g. MRI the brain again), go over the history again, look for tests or diagnoses that weren’t considered, ask for help, and consult a reference or cheat sheet to look for what you missed.
- With any possibility of any paraneoplastic syndrome, particularly anti-NMDAR encephalitis, perform a serious search for neoplasm: CT chest/abdomen/pelvis, testicular ultrasound, either MRI pelvis or transvaginal ultrasound of the ovaries, and sometimes PET scan, although this can be tough to perform due to poor inpatient reimbursement.
- “Classic” NMDAR encephalitis is a younger woman with paranoia, progressing to catatonia and movement disorders, autonomic instability and storming, dyskinesias, hypersalivation, and in late stages, coma. With treatment they regress along the same pathway, and it generally does not recur, although full recovery is not guaranteed and may take many months; the intubated patient usually needs a trach and PEG, and can be difficult to manage due to their autonomic storming and vent dyssynchronies. Without treatment they often never recover.
- With NMDAR and a negative malignancy workup, repeat surveillance imaging is usually warranted to keep searching for tumor.
- Long-term immunosuppression is needed, so a steroid-sparing agent like rituximab is often used.
Dr. Albin’s handy pocket reference to work-up of encephalopathy and diagnosing autoimmune encephalitis.