Recorded presentation by Dr Melanie Alarcio MD from the 2014 FACES Encephalitis Conference.
When it comes to autoimmune encephalitis, misdiagnosis is the norm rather than the exception. Many doctors have never heard of Hashimoto's Encephalitis (HE) or other autoimmune forms of encephalitis (called AEs). AEs are just not something in the awareness of most mainstream doctors.
What is the difference between encephalitis and encephalopathy?
Encephalitis is irritation and inflammation of the brain, usually occurring in an acute manner. Encephalopathy is a diffuse disease of the brain that alters brain function or structure (these definitions came from the NINDS fact sheets and here). Encephalitis is more likely to present with abnormal test results, such as an MRI or spinal tap whereas encephalopathy tends to not show up on tests well, or to show up in subtle ways. Clinical features of encephalitis include a flu-like prodromal state, followed a few days later with headache, fever, vomiting, altered mental status, often seizures, hallucinations, visual disturbances, and may include rigidity of the neck of there is also meningitis. With encephalopathy the hallmark is an altered mental state. Clinical features include confusion, progressive loss of memory and cognitive ability, personality changes, inability to concentrate, lethargy or other progressive loss of consciousness, involuntary movements like myoclonus, tics or tremors, and sometimes seizures. Causes of encephalitis are usually infectious, such as bacteria, viruses, parasites or fungi. They are rarely autoimmune or triggered by medication. Encephalopathy can also be caused by infectious agents, but it is more often the result of metabolic or mitochondrial problems, exposure to toxic substances, trauma, stroke, or brain tumor.
Diagnosis is based on a good clinical history and exam. She says this is a learned and sadly rare skill. Then testing can include CSF analysis, imaging studies like MRI or EEG, antibody testing, serologic testing, and brain biopsy. Encephalitis is first classified as infectious vs non-infectious, if infectious as viral or non-viral. Non-infectious is classified as ADEM, antibody mediated paraneoplastic or non-paraneoplastic, seronegative autoimmune or non-vasculitic autoimmune inflammatory encephalitis. Viruses that can cause encephalitis include herpes simplex, other herpes viruses including varicella zoster, CMV, EBV, HHV6, adenoviruses, influenza A, enteroviruses, poliovirus, measles, mumps, rubella, rabies, arboviruses (including West Nile virus, Japanese B encephalitis, tick-borne encephalitis viruses), bunyaviruses (such as La Crosse strain of California virus), and reoviruses (such as Colorado tick fever).
Non-viral causes include tuberculosis, mycoplasma, listeria, Lyme and coinfections, aspergillis, candida, toxoplasma gondii, and Schistosomiasis, among others (list is at 10:03). Non-infectious causes are more rare, but are becoming less rare recently. ADEM is Acute Demyelinating Encephalomyelitis, it's thought to be a later response to an infection. It is often post-vaccination, which is why it's seen a lot in children.
What is the function of the immune system?
It protects us from infectious micro organisms, and it maintains the "uniqueness" of the individual (for example, rejecting transplants). Because of this second job, one of the fundamental abilities of the immune system is to distinguish "foreign" from "self". Disorders of the immune system include hypersensitivity, autoimmunity, and immune deficiency. It wasn't until the 1950s and 60s that it was widely accepted in mainstream medicine that autoimmunity could be the cause of illness. Autoimmunity can result from genetic predisposition triggered by environmental factors. Autoimmune disease affects between 3 and 8 percent of the general population, with some forms such as adult-onset RA being much more common than other forms such as Systemic Sclerosis.
Autoimmune disorders are not rare, but autoimmune brain disorders ARE rare. The brain was thought to be separated from the immune system for many years, because there are no lymphocytes in the CSF (cerebrospinal fluid), no lymphatic drainage from the brain, and there is a low level of immune-derived molecules in the brain. Also the blood-brain-barrier limits the movement of immune molecules into the brain. There are links between the brain and the immune system, however. The autonomic nervous system modulates the immune system in two ways:
"Sympathetic nervous system (SNS) innervates all lymphoid organs and that catecholamines, the end products of the SNS, modulate several immune parameters. (Lymphoid organs are where immune molecules come from).
And "immune system is tuned by norepinephrine released locally or circulating epinephrine from the adrenal medulla."
Another connection between the brain and the immune system is the neuroendocrine humoral outflow via the pituitary.
At 26:35 is a drawing of how the immune system gets activated by a systemic immune insult, but she says you can substitute stress at that point as well. Stress (or any other insult) triggers monocytes to release interleukin 1 and TNF-alpha. The BBB in the hypothalamus is only a single cell layer, and these pro-inflammatory cytokines can disrupt that thin membrane and enter the hypothalamus. It then triggers the PVN (periventricular nuclei) to release CRF (corticotropin releasing factor) which then acts on the pituitary gland which then releases ACTH to trigger the adrenal gland to release cortisol. This is how stress triggers your immune system and then the immune system affects the brain.
Autoimmune or immune-mediated encephalopathy comprises many different syndromes. Symptoms include inattention, hyperactivity, delusions, paranoia, and hallucinations. They often mimic psychiatric disorders such as schizophrenia and bipolar. These are things that generally onset over days or weeks, not years. At 30:45 is a table showing the similarities between PANDAS, NMDA encephalitis, limbic/paraneoplastic encephalitis, and Hashimoto's Encephalitis. These also share an aspect of movement disorders, which is about dopamine. Dopamine is also involved in the hallucinations and delusions and the emotional component of speech (connection to stuttering?). Treatment for these disorders is all immune based.
She says that in medical school, they are taught that if it is medical, it cannot also be psychiatric, and if it is psychiatric, it cannot also be medical. She says we only have one brain and that one brain gives us both the psychiatric and neurological manifestations. She sees a lot of PANDAS/PANS cases and believes that they are part of a wider group of autoimmune or immune-mediated encephalopathy or encephalitis. She also sees a lot of concussion patients, and they present much the same way.
There is no standard practice guidelines for physicians for these disorders, so each may treat differently. All therapies are immunomodulatory, such as IVIG, plasmapheresis, methotrexate, etc. There are also not standard doses of these medications and treatments. For IVIG, she gives 1 to 1.5 grams per kg per day for 2 days. An immunologist will often give more like 0.5 grams. Recovery occurs over months, not immediately. There can be remission and there can be recurrences. Antibiotics are used in some cases. In addition to treating an underlying infection, they also have non-antimicrobial action. They can also decrease the antigenic load from undetected or asymptomatic infections (in particular Group A Strep. She says strep has been with us for a long time and has evolved ways of avoiding detection in the human body to come back later to get us), they can change inflammatory cell metabolism by altering the cytokines, can allow normalization of tryptophan levels which then affects serotonin levels, and offers neuroprotection by increasing expression of glutamate transporter GLT1.
In concussion, there is something called a glutaminergic surge, which can lead to neurodegeneration and the neuropsychiatric symptoms of concussion. Antibiotics can actually help with that. Ibuprofen can also help by suppressing the production of prostaglandins, and because it can have an anti-inflammatory effect on the blood-brain-barrier, which also helps to limit anti-neuronal antibodies from crossing into the brain.
Her call to action for medical colleagues....listen to the parents, listen to the patient. Don't assume that they are making this up. There is a need to establish a standard of care across medical disciplines.
