Antibody-mediated inflammatory brain disorders

​What are antibody-mediated inflammatory brain disorders?

In antibody-mediated inflammatory disease, B cells (unique white blood cells) produce antibodies against the body's own structures; these are called auto-antibodies. When auto-antibodies bind to these structures, they induce unnecessary inflammation that is directed against healthy tissue. Autoantibodies directed against structures in the brain lead to irritation and swelling of brain tissue. If not treated, long standing inflammation can lead to permanent brain damage and dysfunction.

Antibody-Mediated Normal Immune Response
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Your body’s immune system produces antibodies to "mark" harmful things that enters your body. Special immune cells know what to attack by finding antibodies attached to the surface of these harmful things.
 

Antibody-mediated inflammatory brain diseases are relatively new conditions that were previously under-diagnosed. Recognition and awareness of these conditions is growing however. The following is a list of the currently known antibody-mediated inflammatory brain disorders:

  • Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis
  • Neuromyelitis optica (NMO)
  • Limbic Encephalitis
  • Hashimoto Encephalitis
  • Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS)
Antibody-Mediated Autoimmune Response
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In antibody-mediated inflammatory diseases, the immune system starts creating antibodies against healthy cells. Once marked "bad", the healthy cells become the target of the immune cells’ attack.
 

Your child's condition is not your fault. It is important for you to understand that your child's disease is not due to anything you or a family member may have done. The exact cause of auto-antibody production is not well understood. Various theories have been proposed including the role of infection, malignancy, environmental triggers and genetics.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis

In NMDAR encephalitis, auto-antibodies target the NMDA receptor found on the surface of brain cells. Receptors are very important for cell-to-cell signaling in the brain. It is thought that the action of antibodies binding to the NMDA receptor reduces the number of available receptors on the surface of the brain cells. This has deleterious effects on neuronal signaling, which increase in severity as the number of antibodies increase and the depletion of receptors worsens.

NMDA receptor encephalitis is a relatively new disease, initially discovered in 2007 in female adults. Its incidence has since increased, with more than 400 cases discovered. With such rapid accrual, it is thought to be the most common antibody-mediated brain disease. It primarily affects young adults and children and also occurs with a female predominance of 80%. In adults, the disease is more commonly associated with an ovarian tumor, however this association is rarely seen in young children and infants.

Signs and Symptoms

The disease typically manifests as a continuum of symptoms as the effects of the auto-antibodies on the receptors increase:

  • Cold symptoms: headache, fever, nausea, diarrhea
  • Psychiatric symptoms: behavior abnormalities, hallucinations, paranoia, temper tantrums, insomnia
  • Memory loss, speech problems
  • Decreased responsiveness
  • Seizures, abnormal movements of face and limbs
  • Autonomic dysfunction: breathing instability, rapid heart beat, high blood pressure, increased saliva production, etc.

In young children, the first noticeable presentation is often that of seizures or abnormal movements, preceded by temper tantrums, irritability or hyperactivity. This is likely because young children and infants cannot communicate exactly what they are feeling. The disease is thought to resolve in reverse order, as antibodies are depleted and receptors return to the surface of neuronal cells.

Neuromyelitis Optica (NMO)

In NMO, auto-antibodies target the aquaporin-4 water channel (AQP4), a protein important in maintaining brain water volume. This causes inflammation, degradation of the channel itself and irritation of the surrounding brain tissue.

NMO typically presents in the fourth or fifth decade of life and is less commonly seen in children and seniors. In all age groups, NMO occurs with a female predominance. NMO is most common in people who are non-Caucasian.

Signs and Symptoms

Due to the location of the AQP4 channel in the optic nerves and spinal cord, typical symptoms are reflective of damage to these areas:

  • Hiccoughs
  • Nausea and uncontrollable vomiting
  • Breathing difficulties
  • Blurry vision and eye pain
  • Muscle spasms
  • Burning pain, numbness or paralysis

Other areas of the brain can also be affected, resulting in symptoms such as:

  • Changes in sleep patterns
  • Hypothermia (decrease in core body temperature)
  • Confusion
  • Changes in level of consciousness

Limbic Encephalitis

In limbic encephalitis, auto-antibodies attack a potassium​ channel in the limbic area of the brain, the part of the brain responsible for emotion and memory. This leads to a reduction in the number of potassium channels which decreases the electrical activity of the brain.

Limbic encephalitis is relatively rare in children and adolescents. Two forms exist, one associated with a tumor, seen most often in adults and one that is not associated with a tumor.

Signs and Symptoms

  • rapid cognitive decline
  • behavioural abnormalities
  • Memory loss
  • Seizures

Hashimoto Encephalitis

In Hashimotos encephalitis no auto-antibodies specific to neuronal proteins have been identified. However, the condition is usually seen alongside Hashimoto's Thyroiditis, an autoimmune disorder associated with auto-antibodies against the thyroid gland. Yet, despite the presence of autoantibodies, it is unclear whether they are responsible for patients' neurologic symptoms. Nevertheless, most patients respond to immune-based therapies. This suggests that the disorder does have an underlying, un-identified autoimmune cause.

Hashimoto's encephalitis is a rare complication of Hashimoto's thyroiditis in adults. Its incidence in children is even rarer, but occurs with a female predominance in both populations.

Signs and Symptoms

Symptoms span the neurological and psychiatric spectrum, including:

  • Seizures
  • Confusion and hallucinations
  • Headache
  • Loss of movement (ataxia)
  • Coma

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS)

In PANDAS, no neuronal autoantibodies have been identified. Nevertheless, the condition is still thought be an autoimmune response to a streptcoccal infection in which children suddenly develop obsessive compulsive (OCD) and/or tic disorders. By definition, PANDAS occurs in the paediatric population only.

Signs and Symptoms

Children experience a sudden and dramatic onset of OCD or tic symptoms such as:

  • Persistent thoughts, images, or impulses
  • Repetitive behaviours: excessive washing, checking, touching, counting, ordering
  • Abnormal movement
  • Hyperactivity

Other psychiatric/behavioural symptoms may also be present suddenly such as:

 

​Susanne Benseler, MD

Manisha Sickand, MSc, MD Candidate 2015

Marinka Twilt, MD

 

5/13/2013

 

Notes: