PANDAS variants-
Overlap with- Hashimoto encephalopathy, neurosarcoidosis, NMDAR encephalitis, lupus, and Sjogren’s Syndrome.
PANDAS “plus”-
Overlap with Klein-Levin Syndrome (hypersomnolenic, hyperphagia, hyper-sexual in boys and depression in girls)
Overlap with Ehlers-Danlos Syndrome (EDS 3, chiari malformation, Mast cell Activation Syndrome)
POTS and PANS
Stages of PANDAS/PANS
PANDAS/PANS has 4 stages:
1) cytokine dominant phase (fever-like, alternative fever response)
elevated CAM2K levels on Cunningham panel, low autoantibodies
episodes clearly linked to infectious triggers
2) auto inflammatory phase
elevated CAM2K on Cunningham panel, low-moderate autoantibodies
episodes less clearly linked to infection
other autoantibodies may start to show, such as positive ANA and thyroid
3) auto antibody dominant phase
CAM2K elevated on Cunningham panel, high levels of autoantibodies
While infections exacerbate symptoms, episodes not linked to infectious triggers
Harder to reverse
4) irreversible brain injury
The basal ganglia and thalamus are targeted
Takes years to get to this stage
Treating stage 1-
Treat as a fever. NSAIDs work well (Motrin, Aleve, Celebrex). Find the trigger, treat the trigger- the right antibiotic works incredibly well (or antiviral). Treat prophylactically to avoid future episodes. Avoid neuropsychiatric agents of possible.
Treating Stage 2-
The disease has probably been going on for a few years. Antibiotics no longer as effective, or effective at all. Treat as an inflammatory disease. NSAIDs still helpful. If possible, find and treat the trigger. Immunomodulatory treatment helpful, such as IVIG, especially in kids with an immunodeficiency. Oral or intravenous steroids. Avoid neuropsychiatric meds if possible.
Treating stage 3-
The disease has been going on for at least a few years. Antibiotics no longer work. Treat as an autoantibody disorder (such as Myasthenia Gravis). If possible, find and treat the trigger. NSAIDs may still provide acute relief. Stronger immunomodulatory treatment called for, once infection is treated, such as IVIG, cellcept, rituximab, immunosuppressive agents. Avoid neuropsychiatric meds if possible,
Treating stage 4-
Disease has been progressing for at least 5 years. Antibiotics no loner work. Look for metabolic disease mimic. Acute relief from NSAIDs. IVIG, Cellcept, Rituximab, other immunosuppressants may help (not in slide, but plasmapheresis). Avoid neuropsychiatric meds if possible.
The role of histamine
He discusses this study L-histidine decarboxylase and Tourette's syndrome.
"Tourette's syndrome is a common developmental neuropsychiatric disorder characterized by chronic motor and vocal tics. Despite a strong genetic contribution, inheritance is complex, and risk alleles have proven difficult to identify. Here, we describe an analysis of linkage in a two-generation pedigree leading to the identification of a rare functional mutation in the HDC gene encoding L-histidine decarboxylase, the rate-limiting enzyme in histamine biosynthesis. Our findings, together with previously published data from model systems, point to a role for histaminergic neurotransmission in the mechanism and modulation of Tourette's syndrome and tics."
There is only ONE HDC gene, so polymorphisms in this gene affect many cells including neurons and basophils. TS/OCD is tied to defective brain histamine synthesis. This also implies defective histamine synthesis in the gut and immune system as well. All brain histamine originates in the tuberomammilary nucleus (TN, what he refers to as the VTN and calls the "soul" of PANDAS), not the basal ganglia.
And this study Neural circuitry engaged by prostaglandins during the sickness syndrome.
"During illnesses caused by infectious disease or other sources of inflammation, a suite of brain-mediated responses called the sickness syndrome occurs, which includes fever, anorexia, sleepiness, hyperalgesia and elevated corticosteroid secretion. Much of the sickness syndrome is mediated by prostaglandins acting on the brain and can be prevented by nonsteroidal anti-inflammatory drugs, such as aspirin or ibuprofen, that block prostaglandin synthesis. By examining which prostaglandins are produced at which sites and how they interact with the nervous system, researchers have identified specific neural circuits that underlie the sickness syndrome."
The prostaglandin PGE2 regulates the fever response via neuronal pathways in the hypothalamus. The prostaglandin PGD2 promotes sleep during inflammation by suppressing the TN from producing histamine. He proposes that in the alternate fever model PGE2 stimulates the TN to produce histamine rather than the stimulating neurons in the median preoptic nucleus from allowing fever to occur.
To summarize the alternate fever model of PANDAS/PANS
The cytokine milieu associated with this variant phenotype results in an imbalance of action of PGE2 on the MnPO and VTN, with an increase in effect on the latter versus the former.
Chronic over-stimulation of the VTN results in brain H3-receptor dysregulation and dysregulation of release of neurotransmitters (i.e. dopamine, serotonin, norepinephrine, and others).
Due to the widespread “pervasive” neuroanatomical connections of the VTN, one sees a “pervasive behavioral syndrome” following common infections.
Autoantibodies play an ancillary role in this model."
