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What is a differential diagnosis? 




Differential diagnosis is a process wherein a doctor differentiates between two or more conditions that could be behind a person’s symptoms. When making a diagnosis, a doctor may have a single theory as to the cause of a person’s symptoms. They may then order tests to confirm their suspected diagnosis. Often, there is no single laboratory test that can definitively diagnose the cause of a person’s symptoms. This is because many conditions share the same or similar symptoms, and some present in a variety of different ways. A person can have all the symptoms in autoimmune encephalitis and not have the disease. To make a diagnosis, a doctor may need to use a technique called differential diagnosis.

Differential diagnosis involves making a list of possible conditions that could be causing a person’s symptoms. The doctor will base this list on information they gain from:

  • the person’s medical history, including their self-reported symptoms
  • physical examination findings
  • how the patient presents clinically (the symptoms they display)
  • diagnostic testing

Less commonly in the diagnostic approach, a doctor may have one theory about the cause of a person’s symptoms and test for that one condition. However, many conditions share some of the same or similar symptoms. This makes the underlying condition difficult to diagnose using a nondifferential diagnostic approach. A differential diagnostic approach is helpful when there may be multiple potential causes to consider.

The goals of differential diagnosis are to:

  • narrow down the working diagnosis
  • guide medical evaluation and treatment
  • rule out life threatening or time critical conditions
  • enable the doctor to make the correct diagnosis


Differential diagnosis can take time especially when dealing with an uncommon disease that is very complex to diagnosis such as autoimmune encephalitis. For a doctor to determine the correct diagnosis, they will follow the steps below.


Take a medical history


When preparing for differential diagnosis, a doctor will need to take a person’s full medical history. Some questions they may ask include:

  • What are your symptoms?
  • How long have you been experiencing symptoms?
  • Do you have a family history of certain conditions?
  • Have you traveled out of the country recently?

It is important that a person answers all questions honestly and in as much detail as possible.


Perform a physical exam


Next, a doctor will want to perform a basic medical examination that will include how the patient is clinically presenting.


 Conduct diagnostic tests


After taking a medical history and performing a physical examination, the doctor may have some ideas as to what may be causing a person’s symptoms.

They may order one or more diagnostic tests to rule out certain conditions.


Send the person for referrals or consultations

Each test result rules out possible culprits and guides the doctor as to what to test for next. In some cases, the doctor may feel that they do not have the specific expertise to diagnose the exact cause of a person’s symptoms. In such cases, they may refer the person to a specialist for a second opinion. It is not uncommon for multiple doctors to review one patient during differential diagnosis.

Encephalitis has a broad differential diagnosis

The differential diagnosis for encephalitis is very broad and includes infections, toxic-metabolic encephalopathy, mitochondrial disorders, nutritional deficiencies, vascular disorders, malignancy, and demyelinating disorders. Clinicians should be particularly concerned about ruling out an infectious process given the immunotherapies utilized to treat AE. Infections to consider include herpes simplex virus encephalitis, human herpesvirus 6, human immunodeficiency virus, fungal infection (eg, cryptococcal), mycobacterial infection, Whipple disease, and neurosyphilis.

In general, viral infections usually cause a more profound CSF pleocytosis (a white blood cell count of 50–100/μL). Bacterial or mycobacterial infections can have a lower of CSF glucose concentration, whereas AE usually has normal glucose levels.

Overall, careful examination usually reveals subtle neurologic deficits that should prompt further evaluation for AE. Diagnostic red flags include newly occurring epileptic seizures, movement disorders, and neurocognitive symptoms, especially in the setting of MRI or CSF abnormalities.

It should be mentioned that the prevalence of primary psychiatric disorders is much higher than the prevalence of AE. For example, the overall prevalence of schizophrenia, with incidence peaking in young adults, is estimated to be 2.7 to 8.3 per 1,000, whereas the overall prevalence of AE is 13.7 per 100,000. Thus, in a young patient with new mood disorder, a primary psychiatric diagnosis remains more likely than AE.

While patients with a preexisting psychiatric disorder can develop a concomitant autoimmune condition, it should also be mentioned that a specific isolated psychiatric AE phenotype has not emerged in the literature despite extensive investigations. (1) 

Reference: Antibody-mediated autoimmune encephalitis: A practical approach,

Justin R. Abbatemarco, MD, Chen Yan, MD, Amy Kunchok, MBBS and Alexander Rae-Grant, MD, FAAN, FRCPC
differential diagnosis

Our website is not a substitute for independent professional medical advice. Nothing contained on our website is intended to be used as medical advice. No content is intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for your own health professional's advice. Although THE INTERNATIONAL AUTOIMMUNE ENCEPHALITIS SOCIETY  provides a great deal of information about AUTOIMMUNE ENCEPHALITIS, all content is provided for informational purposes only. The International Autoimmune Encephalitis Society  cannot provide medical advice.

International Autoimmune Encephalitis Society is a charitable non-profit 501(c)(3) organization founded in 2016 by Tabitha Andrews Orth, Gene Desotell and Anji Hogan-Fesler. Tax ID# 81-3752344. Donations raised directly supports research, patients, families and caregivers impacted by autoimmune encephalitis and to educating healthcare communities around the world. Financial statement will be made available upon request.

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