Research Updates: At the Crossroads of Infection, Inflammation, and Mental Health

Jennifer Frankovich, MD, MS, dives into the intersection of infection, inflammation, and mental health. She discusses the increase in recognition of this critical overlap over the last decade, highlighting how systemic inflammatory conditions have the highest rate of co-occurring psychiatric disorders. The speaker outlines ten inflammatory diseases that frequently co-occur with mental health conditions, including spondyloarthritis, psoriasis/psoriatic arthritis, Behçet’s Syndrome, Sjögren’s disease, Scleroderma, CNS Vasculitis, Sydenhams’ Chorea, and Lupus. Frankovich underscores the connection of Streptococcal infections to many of these inflammatory conditions, noting their similarities to PANS and challenges with diagnosis. She provides thanks and acknowledgments before the Q&A. 

This is a follow-up to our June 12, 2024 webinar featuring Dr. Jennifer Frankovich, Ayan Mondal, Ph.D., and Noor A. Hussein, Ph.D.

In this Webinar

1:20 – Inflammation and mental health
3:50 – Spondyloarthritis (SpA)
11:00 – Psoriasis/Psoriatic Arthritis
16:05 – Behçet’s Syndrome
19:25 – Brain parenchymal disease
21:15 – Non-parenchymal disease
22:25 – Sjögren’s disease
24:05 – Scleroderma
25:50 – CNS Vasculitis
26:25 – Sydenhams’ Chorea
37:00 – Erythema Marginatum
38:50 – Strep infections and mental health
42:00 – Lupus
44:55 – Q&A

Inflammation and mental health

Over the last decade, recognition of the overlap between rheumatological/inflammatory disorders and mental health conditions has significantly increased. Frankovich notes common inflammatory diseases that co-occur with psychiatric symptoms, including those caused by small-vessel vasculitis, autoimmune encephalitis, basal ganglia inflammation, and white matter inflammation (1:20). Most commonly, she continues, systemic inflammatory conditions like psoriasis/psoriatic arthritis, and irritable bowel syndrome (IBS) have the highest rates of co-occurring psychiatric disorders (3:30). She outlines ten (10) specific disorders, how they present, and how clinicians/practitioners can test for them.

The odd couple?—Hardly: The emerging overlap between rheumatology and psychiatry (Taylor & Jain, 2017)

Spondyloarthritis 

Spondyloarthritis (SpA) can cause microscopic spinal inflammation that is not often perceptible on imaging until decades later. It is characterized by pain and stiffness in the morning and after prolonged stationary positions. Frankovich explains that 40% of patients with SpA also experience depression, anxiety, fatigue, and brain fog and that adults with SpA have a higher prevalence of OCD, anger/hostility, and deliberate self-harm versus controls (3:50). The speaker notes that children with psychiatric diagnoses may not be able to articulate pain and stiffness, so practitioners must look for clues such as stiffness walking, axial and peripheral stiffness, iliac pain and tenderness, and specific foot pains. Psoriasis and bowel inflammation also commonly co-occur with SpA. Frankovich underscores the high heritability of SpA and suggests observing parental symptoms when diagnosing children (7:15). 

Psoriasis/Psoriatic Arthritis

Psoriasis and psoriatic arthritis have significant overlap with psychiatric disorders, especially bipolar, depression, and anxiety. The speaker explains that pain from arthritis can seem out of proportion, so patients are often dismissed. Frankovich notes specific ultrasounds that can be used to identify inflammation in discrete areas of the body and reiterates how psychiatric conditions may keep patients, especially children, from complaining of their pain, making a diagnosis even more challenging (11:00). Common sites for psoriasis include behind the ears, on the scalp, around the belly button. She warns against mistaking Onycholysis for fungal nail infections and notes that streptococcal infections can trigger arthritis flares (13:35). 

Behçet’s Syndrome

The speaker describes Behçet’s Syndrome as a multisystem inflammatory disease where 10% of patients have neurological diseases perceptible on an MRI and 40% have psychiatric disorders. Other symptoms can include recurrent oral ulcers, ocular inflammation in the anterior portion of the eye, and potential scarring from genital ulcers. Behçet’s Syndrome is a type of transient arthritis where flareups, often triggered by intense immune responses to infection, can last from one to three weeks (16:05). Frankovich notes that when vascular inflammation is present in both arteries and veins, this nearly always indicates Behçet’s Syndrome. Pathergy, or blistering at the blood draw site, is also a strong indicator (18:25). 

Brain parenchymal disease

Brain parenchymal disease (BPD) is characterized by a subacute onset of multi-focal inflammatory legions, which an MRI can miss if it is not conducted at the time of a new deficit. In many cases, the MRI reflects non-specific white matter changes that do not rule out BPD in and of themselves. Some patients also suffer from headaches, behavior changes, and cognitive dysfunction, which can lead to temporary encephalopathy, seizures, and psychosis. The presenter underscores the importance of early diagnosis and treatment but notes that BPD is difficult to diagnose because legions are temporary and appear in different places each time (19:25). 

Non-parenchymal disease

Non-parenchymal diseases involve the brain’s venous systems. Cerebral venous thrombosis, or severe headaches, must be assessed using imaging that highlights the venous system (e.g., MRV). Non-parenchymal diseases often co-occur with fibromyalgia (18 – 37%), parietal cell autoantibodies, vitamin deficiencies (especially B,) and bowel ulcers or IBS (21:15). 

Sjögren’s disease

Frankovich defines Sjögren’s disease as a systemic rheumatologic condition that often presents with dry eyes and mouth and a lot of autonomic nervous system dysfunction such as altered vascular tone, esophageal contractility (trouble swallowing), cardiac rhythm abnormalities, and neuropathic symptoms (i.e., burning, tingling, or numbness). Co-occurring psychiatric disorders make it challenging to self-advocate. The speaker suggests running a mucosal biopsy of the lip to assess salivary gland inflammation if Sjögren’s disease is suspected (22:25). 

Scleroderma

Scleroderma is a systemic sclerosis that causes widespread vascular dysfunction and progressive fibrosis of the skin and internal organs. Over many years, the speaker explains, a person’s skin starts to harden. Early signs in children include Raynauds (cold, white hands) and abnormal nail fold capillaroscopic. She highlights that manifestation may precede the full disease by years, so it is critical to follow patients closely (24:05). 

Personality structure disturbances and psychiatric manifestations in primary Sjögren’s syndrome (Drosos et al., 1989)

CNS Vasculitis

CNS vasculitis is a very rare type of inflammation focused on the brain. It is perceptible on MRI scans and should be considered when children present with new-onset headaches and behavior changes (25:50). 

The spectrum of CNS vasculitis in children and adults (Twilt & Benseler, 2012)

Sydenhams’ Chorea

Sydenhams’ Chorea (SC) presents with three critical components: emotional lability, hypotonia (weak muscles), and chorea (involuntary, brief, random, and irregular movements of the limbs and face). In children, this can look like continuous restlessness (26:25). Frankovich explains that accompanying psychiatric symptoms are similar to what we see in PANS. For example, 60% of patients with SC have OCD at onset, and 100% have it at relapse. Other symptoms include outbursts of inappropriate behavior or mismatched emotions (easy crying or inappropriate laughing), irrational fears that can lead to delusions, anxiety, personality changes, and night terrors (28:08). Other presentations include difficulty keeping arms up or hyperactive reflexes (33:40). 

The presenter notes that the line between what is and is not SC is very blurry, making it hard to detect and diagnose. One of the earliest studies (1926) notes that, in children, nuanced chorea is always Sydenhams, so practitioners should always treat for strep infection and clear it out of the house. According to the study, emotional lability is the most constant observation, along with extreme personality changes where individuals become aggressive and irritable, which is very similar to how PANS presents (30:00). 

Children often cover up their chorea, so clinicians must actively look for muscle use abnormalities. Simple tests for chorea include the milkmaid’s grip and darting tongue. Because psychiatric symptoms like OCD can start two to four weeks before chorea, children who present with acute-onset OCD should be re-evaluated over at least one month (31:25). The onset of chorea can occur anywhere between one and eight months after a strep infection, meaning that ASO and DNASE titers may be normal during assessments (33:40). 

The presence of acute rheumatic fever can also support an SC diagnosis, but it is not necessary. However, the speaker warns that mild cases of SC without other manifestations of acute rheumatic fever may be mistakenly ascribed to behavior or emotional disorders, restlessness, or clumsiness. She reiterates the need for careful evaluation (36:10). 

Neuropsychiatric Aspects of Chorea in Children (Ebaugh, 1926)

The Prevalence of Neuropsychiatric Disorders in Sydenham’s Chorea (Ridel et al., 2010)

Obsessive compulsive behavior, hyperactivity, and attention deficit disorder in Sydenham chorea (Maia et al., 2005)

High prevalence of obsessive-compulsive symptoms in patients with Sydenham’s chorea. (Swedo et al., 1989)

Obsessive-Compulsive and Related Symptoms in Children and Adolescents With Rheumatic Fever With and Without Chorea: A Prospective 6-Month Study (Asbahr et al., 1998)

Sydenham’s Chorea: Physical and Psychological Symptoms of St Vitus Dance (Swedo et al., 1993)

The Emotional Correlates of Sydenham’s chorea (Freeman et al., 1963)

Mental Symptoms of Acute Chorea (Diefendor, 1912)

Rheumatic fever (Stollerman, 1997)

Erythema Marginatum 

Erythema Marginatum is a rash or skin lesion that occurs in SC and is brought out with heat (warm blankets or bath). Frankovich describes a case study of a 16-year-old with a long history of regressive behavior deterioration. He was initially diagnosed with SC; however, due to a lack of valve involvement, the diagnosis was removed. When he later presented with catatonia, clinicians wrapped him in warm blankets for 10 – 20 minutes and then observed his torso and limbs for rash patterns. The speaker notes that Erythema Marginatum patterns change every few minutes and that no other condition presents with such a rash (37:00). 

Streptococcal infections, inflammation, and mental health

A recent population-based study on the association of streptococcal infection and mental disorders found the primary outcome of strep infections was a diagnosis of mental disorders, OCD, or tics (38:50). The speaker says it can be difficult to know if strep played a role in any child’s behavior, so we must rely on epidemiologists continue educating practitioners about the link between strep and mental disorders, especially OCD. 

A smaller study that compared school strep swabs to behaviors found a high correlation between positive strep throat cultures and the presence of tics, adventitious movements, and problem behaviors. Further, if the strep was recurring, the risk for abnormal movements was increased (40:00). Many animal models have also shown this correlation. 

 Association of streptococcal throat infection with mental disorders (Orlovska et al., 2017)

Relationship of Movements and Behaviors to Group A Streptococcus Infections in Elementary School Children (Murphy et al., 2007)

CNS Autoimmune Disease after Streptococcus Pyogenes Infections: Animal Models, Cellular Mechanisms and Genetic Factors (Cutforth et al., 2016)

Lupus 

Lupus, though a common condition, is relatively rare in children. However, 25% of children with Lupus also have neuropsychiatric symptoms such as headaches (66%), psychosis (36%), and cognitive dysfunction (27%). Similar to PANS, Lupus patients commonly have arthritis, small vessel vasculitis, and high immune complexities. They are also 10 – 15 times more likely to have OCD compared to patients without Lupus (42:00). 

Resources

Frankovich thanks viewers and acknowledges research contributors. For more information on her research, visit med.stanford.edu/PANS. During the Q&A (44:55), the speaker answers questions about diagnosis, overlapping conditions, and much more.

Originally posted on October 1, 2024