Mood disorders and inflammation: High cortisol and low serotonin (Part 2 of 4)

There are multiple suspect pathways for causation of mood dysregulation in the setting of inflammation. One well described model hinges upon the ability of inflammatory mediators to impact the HPA axis, a system of hormone release that drives many physiologic functions in addition to the stress response.  Briefly, the central pathway of the HPA axis is that CRH causes production of ACTH, which causes production of cortisol, a stress hormone and a very potent anti-inflammatory under most circumstances.  Many molecules can affect the signaling of the HPA axis and contribute to inappropriate hormone regulation.

IL-1, IL-6, TNF and IFN-a are all inflammatory mediators released by mast cells and other cells. These mediators all activate the HPA axis, resulting in high production of CRH, ACTH and cortisol via a series of intertwined mechanisms. At the same time, inflammation also makes cortisol less effective.  There are several ways for this to occur. Inflammation can cause cells to make fewer receptors for cortisol, meaning that no matter how much cortisol is made, only a small fraction will be able to act on cells.  Persistently high cortisol levels decrease production of other anti-inflammatory molecules and molecules that mediate the anti-inflammatory action of cortisol.  High cortisol also tells the HPA axis that it doesn’t need to make more cortisol, so even though more may actually be necessary, your body doesn’t know that.

All of these factors coalesce to form a reality where cortisol may be elevated but with little anti-inflammatory effect because of the changes I mentioned above. High cortisol is associated with mood symptoms.

Decrease of serotonin activity is also seen in mood disorders. Tryptophan is a precursor to serotonin, a hormone and neurotransmitter that heavily regulates mood.  Cortisol increases the activity of a molecule called tryptophan 2,3-dioxygenase (TDO), which removes the amino acid tryptophan from the pool of molecules to break down. Inflammatory molecules like interferon increase activity of the enzyme IDO, which decreases serotonin production.  IDO breaks down tryptophan to molecules that cannot be made into serotonin, such as kynerenin and quinolonic acid.  These metabolites have been observed as elevated in models of depression and anxiety.

Another way that inflammatory mediators affect the action of serotonin is to hasten its degradation. Both TNF and IL-6 increase the breakdown of serotonin to 5-HIAA.

References:

Furtado M, Katzman MA. Examining the role of neuroinflammation in major depression. Psychiatry Research 2015: 229, 27-36.

Rosenblat JD, et al. Inflamed moods: a review of the interactions between inflammation and mood disorders. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2014; 53, 23-34.

Mood disorders and inflammation: Mediators (Part 1 of 4)

Mood disorders are the leading cause of disability in many countries around the world. Depression alone affects a staggering number of people, currently thought to be about 350 million people worldwide.  Its prevalence and diagnosis is increasing to such an extent that the WHO expects it to be the primary cause of global disease burden in less than 15 years.

Mood disorders are commonly found in patients diagnosed with inflammatory conditions.  Cardiovascular disease, diabetes, metabolic syndrome, asthma, allergies and many autoimmune diseases co-occur with these psychiatric conditions.  While providers are often tempted to attribute depression, anxiety and maladaptive behaviors to the stress of having chronic health issues, a significant body of evidence firmly supports the idea that mood disorders are themselves inflammatory conditions and therefore biologically ordained. Furthermore, having a mood disorder can affect prognosis in some diseases.

A number of inflammatory molecules participate in immune response, including histamine, prostaglandins, bradykinin, leukotrienes, CRP, interferon, cortisol and cytokines.  These substances are released in response to physical stresses such as infection, trauma or disease process.  Psychological stress also triggers inflammatory response with increases of molecules such as IL-6, IL-1b, TNF and CRP.

Several studies have definitively found that mood symptoms are associated with increased levels of inflammatory markers.  PGE2, CRP, TNF, IL-1b, IL-2 and IL-6 were all elevated in both peripheral blood and cerebrospinal fluid in patients with major depressive disorder.  A massive 25-80% of hepatitis C patients experience depressive symptoms when they begin treatment with interferon, a potent inflammatory molecule. Elevated interferon and IL-2 levels have been observed early in the depressive event.

In human patients, studies have simulated an inflammatory response by inoculation with toxins, proteins associated with infectious organisms, or interferon. In one study, an inflammatory response was provoked by inoculation with Salmonella endotoxin.  While they suffered no physical symptoms, anxiety, depressed mood and decreased memory function was observed along with elevated TNF, IL-6 and cortisol levels.  Another study found that inoculation with LPS (a substance found in bacterial cell membranes) triggered a dose dependent increase in IL-6, IL-10, TNF, cortisol and norepinephrine, which in turn triggered a dose dependent increase in anxiety, “poor mind” and decreased long term memory functions.

References:

Furtado M, Katzman MA. Examining the role of neuroinflammation in major depression. Psychiatry Research 2015: 229, 27-36.

Rosenblat JD, et al. Inflamed moods: a review of the interactions between inflammation and mood disorders. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2014; 53, 23-34.

 

Symptoms, mediators and mechanisms: A general review (Part 2 of 2)

 

Gynecologic symptoms    
Symptom Mediators Mechanism
Irregular and painful menstruation Histamine (H1), bradykinin Smooth muscle constriction
Uterine contractions Histamine (H1), serotonin, bradykinin Smooth muscle constriction

Increased estrogen

 

 

Neurologic symptoms    
Symptom Mediators Mechanism
Appetite dysregulation Histamine (H1), histamine (H3), leptin Dysfunctional release of neurotransmitters, suppression of ghrelin
Disorder of movements Histamine (H2), histamine (H3) Dysfunctional release of neurotransmitters, increases excitability of cholinergic neurons
Memory loss Histamine (H1), histamine (H3) Dysfunctional release of neurotransmitters
Headache Histamine (H1), histamine (H3), serotonin (low) Dysfunctional release of neurotransmitters

 

Low serotonin

 

Decreased blood flow to brain

Depression Serotonin (low), TNF, histamine (H1) Low serotonin

Disordered release of dopamine

Irregular sleep/wake cycle Histamine (H1), histamine (H3), PGD2 Dysfunctional release of neurotransmitters
Brain fog Histamine (H3), inflammatory cytokines Dysfunctional release of neurotransmitters, neuroinflammation
Temperature dysregulation Histamine (H3) Dysfunctional release of neurotransmitters, dysfunctional release of catecholamines

 

 

Miscellaneous symptoms    
Symptom Mediators Mechanism
Bleeding diathesis (tendency to bleed easily) Tryptase, heparin Participation in anticoagulation pathways

Neuropsychiatric features of mast cell disease: Part 2 of 2

Mast cell activation can induce neuropsychiatric symptoms. Degranulation has been linked previously to headache. It is possible that peptidergic and cholinergic neurons receive mast cell mediators and that this plays a role in headache pathology.  TNF is speculated to participate in depression.  Histamine may cause memory deficits, although there is conflicting information on this topic. Some patients have improvement in neuropsychiatric symptoms with antihistamines.

Mastocytosis patients who have GI and neuropsychiatric symptoms often have low serum serotonin.  Tryptophan is a precursor to serotonin. Plasma tryptophan is also often low in mastocytosis patients, while plasma IDO1 (indoleamine-2,3-dioxygenase 1) activity is higher. IDO1 breaks down tryptophan through an alternate pathway that does not form serotonin. In this pathway, IDO1 breaks down tryptophan, forming kynurenic acid and quinolinic acid.  The accumulation of these substances could explain the fatigue and cognitive impairment in mastocytosis patients.  Low tryptophan and low serotonin in this population were associated with perceived stress and depression.

Treatment of neuropsychiatric symptoms in mast cell patients can include a variety of medications.   SSRI medications can reduce fatigue and depression in some inflammation models.  Some mast cell patients take these medications, usually with low starting doses in case mast cell degranulation in these people has conversely led to higher serotonin levels.  Bupropion, SNRIs and tricyclic medications are also commonly used for depressive symptoms in many chronic illness populations.

Some tricyclic antidepressants have antihistamine properties, with doxepin being a common choice.  Another tricyclic, amitriptyline, can inhibit release of mast cell mediators. Mianserin and mirtazapine can be prescribed for insomnia but also have antihistamine properties. Aprepitant could potentially be used in treatment of depression and cognitive impairment in mastocytosis and MCAS patients. Prochloperazine also decreases mast cell mediator release. Amantadine has improved depression and fatigue symptoms in multiple sclerosis patients. Inhibition of TNF with infliximab has improved depression in patients with high levels of inflammation.

Kynurenic acid, formed in the alternate tryptophan breakdown pathway described above, can block acetylcholine receptors, causing neurologic symptoms.  A7 agonists like nicotine could potentially overcome this effect.  Quinolinic acid binds at the NMDA receptor, cause neurologic symptoms.  Ketamine, an NMDA antagonist, can produce significant improvements in depressive symptoms in treatment resistant depression. As quinolinic acid is typically present in higher levels than kynurenic acid in mastocytosis patients, ketamine might offer a treatment for these patients with depression and high perceived stress.

Masitinib, a tyrosine kinase inhibitor, was shown to decrease depression, anxiety and cognitive difficulties in a significant amount of mastocytosis patients. Mindful meditation may also help patients to lessen activation caused by psychological stress and therefore decreasing biological stress.

References:

Georgin-Lavialle S, et al. Mastocytosis in adulthood and neuropsychiatric disorders. Translational Resarch 2016; x:1-9.

Georgin-Lavialle S, et al. Leukocyte telomere length in mastocytosis: correlations with depression and perceived stress. Brain Behav Immun 2014; 35: 51-57.

Moura DS, et al. Neuropsychological features of adult mastocytosis. Immunol Allergy Clin North Am 2014; 34(2): 407-422.

Moura DS, et al. Depression in patients with mastocytosis: prevalence, features and effects of masitinib therapy. PLoS One 2011, 6: e.26375.

Moura DS, et al. Evidence for cognitive impairment in mastocytosis: prevalence, features and correlations to depression. PLoS One 2012, 7: e.39468.

Smith JH, et al. Neurologic symptoms and diagnosis in adults with mast cell disease. Clin Neurol Neurosurg 2011, 113: 570-574.

Neuropsychiatric features of mast cell disease: Part 1 of 2

The fact that psychiatric symptoms occur as a function of mast cell disease on the nervous system is common knowledge to patients but less acknowledged by providers.  A significant population of mast cells is found in the brain in close association with both blood vessels and nerve cells.  Mast cells are present in large numbers in the hypothalamus, which regulates stress response, emotion and cognition; the amygdales, near the pituitary gland; and the thalamus.  Lesions and structural changes in the thalamus have previously been associated with altered perception of pain and emotional reactivity.

One study found that in a group of 88 patients with indolent systemic mastocytosis (ISM) and cutaneous mastocytosis (CM), 75% reported depressive symptoms.  In another study, a group of 288 mastocytosis patients had a prevalence of 60% depressive and anxiety-type symptoms.  The depressive symptoms seen most often in mastocytosis patients are affective and cognitive symptoms (depressed mood, low motivation, feelings of guilt and failure; and anxio-somatic symptoms (physical and mental effects of anxiety, insomnia).  Psychomotor difficulties (slowing of thought processes and/or neurologic control of movement) and lack of insight were rare in these patients.

Depression is often assessed using the Hamilton Depression Rating Scale.  This tool may not be ideal for use in mast cell patients because the somatic symptoms correlated with depression are often the same as physical symptoms of mast cell disease.  When excluding symptoms that could be from mastocytosis rather than depression, patients still had a high prevalence of sadness and loss of motivation.

One mastocytosis cohort reported 38.6% had cognitive impairment of some kind. Inability to focus and pay attention is the cognitive symptom most commonly reported by mastocytosis patients.  This was not linked to depression, age, education or staging of mastocytosis.  Importantly, it was also independent of amount of antihistamine use.  Memory impairment was also not related to age or education.  Cognitive difficulties were found to be much more prevalent in mastocytosis patients than in other chronic disease populations.

Fatigue is a common neuropsychiatric symptom for mast cell patients and has been seen in populations with both mastocytosis and mast cell activation syndrome.  Patients who have moderate to severe fatigue often experience pain and cognitive deficits.  The level of fatigue can be disabling as it makes it difficult to focus or perform even simple tasks.

35% of mastocytosis patients in one study reported 35% had either acute or chronic headaches.  37.5% had migraines, while 17.2% had tension type headaches.  Headache patients often reported episodic flushing or itching at the time of the headache. In the migraine group, 66% experienced aura symptoms.  Overall, 39% of patients in this group with or without migraines experienced aura symptoms, usually visual.

Exaggeration of the stress response could explain neuropsychiatric symptoms in mast cell patients. In one population, 42% of patients perceived their stress level to be high. Persistent stress response could lead to negative emotions.  These symptoms could be reinforced by mast cell hyperactivity in the brain, which can affect stress response, emotionality and cognition.

References:

Georgin-Lavialle S, et al. Mastocytosis in adulthood and neuropsychiatric disorders. Translational Resarch 2016; x:1-9.

Georgin-Lavialle S, et al. Leukocyte telomere length in mastocytosis: correlations with depression and perceived stress. Brain Behav Immun 2014; 35: 51-57.

Moura DS, et al. Neuropsychological features of adult mastocytosis. Immunol Allergy Clin North Am 2014; 34(2): 407-422.

Moura DS, et al. Depression in patients with mastocytosis: prevalence, features and effects of masitinib therapy. PLoS One 2011, 6: e.26375.

Moura DS, et al. Evidence for cognitive impairment in mastocytosis: prevalence, features and correlations to depression. PLoS One 2012, 7: e.39468.

Smith JH, et al. Neurologic symptoms and diagnosis in adults with mast cell disease. Clin Neurol Neurosurg 2011, 113: 570-574.

The Sex Series – Part Six: Male pelvic dysfunction and mast cells

Chronic pelvic pain syndrome (CPPS) affects about 15% of male patients and 90% of patients with chronic prostatitis. Patients with these conditions experience pain in the pelvis, abdomen and genitalia, as well as urinary tract symptoms without evidence of infection. Pain can be intermittent or constant, and can interfere with daily activities including sitting, standing, urination and defecation.

CPPS also causes sexual symptoms. Painful ejaculation, erectile dysfunction, and other types of ejaculation dysfunction are all common in this patient group.  In one study, 40% of patients with CPPS were found to have erectile dysfunction.  In another, 72% of patients reported either erectile dysfunction or difficulty with ejaculation.

Pelvic floor dysfunction is a component of CPPS. Many of these patients have abnormally tense pelvic floor muscles, which can cause muscle spasm and obstruct bloodflow. CPPS patients are more likely than healthy controls to have vascular dysfunction associated with nitric oxide level. In a group of 146 patients with CPPS and verified pelvic floor spasm, 56% experienced painful ejaculation.  Visceral and myofascial pain and spasm of the muscles in the pelvic floor contribute to CPPS.  While pelvic floor dysfunction has been well researched for female patients, there are far fewer studies on pelvic floor dysfunction in men.  Biofeedback and pelvic floor physical therapy can resolve issues with erectile dysfunction and other sexual issues.

IL-17, expressed by special T cells called Th17 cells, is required to develop CPPS-like conditions in animal models. IL-17 triggers mast cell degranulation and secretion of many inflammatory molecules.  A number of mast cell mediators are elevated in patients with CPPS. IL-1b, TNF, IL-6 and IL-8 are higher in seminal fluid of these patients.  CCL2 and CCL3 expression is also increased. In the prostate of animals with a CPPS model, TNF, IL-17a, IFN-γ and IL-1b are all increased.

Tryptase has been found to induce pelvic pain. Levels of tryptase and carboxypeptidase A3 are higher in CPPS patients than in healthy controls.  Tryptase binds to a receptor called PAR2.  When tryptase binds to this PAR2 receptor, it is thought that it makes nerves oversensitive. If the PAR2 receptor is blocked, pelvic pain is mitigated.  In animal models where they cannot make tryptase-like products, pelvic pain does not develop in CPPS.

Nerve growth factor (NGF) is a mast cell mediator that has been implicated in CPPS. It is elevated in seminal plasma of CPPS patients and directly correlates with pain level. It is thought that NGF makes the peripheral nerves oversensitive and causes more nerve cells than usual to be present. NGF and tryptase were elevated in prostate secretions of most CPPS patients in a small patient group. Of note, NGF release occurs and increases weeks after initial symptoms.

In animal models, injecting cetirizine (H1 antihistamine) into the peritoneal cavity decreased pain by about 13.8%; ranitidine (H2 antihistamine), 6.1%; cromolyn, 31.4%. A combination of all three decreased pain by 69.3%. When cromolyn and cetirizine were used together, larger pain relief was achieved than when used individually, but this was not seen when using ranitidine and cromolyn together.  These data suggest that H2 signaling is not a major contributor in chronic pelvic pain in male patients.

Pelvic floor dysfunction is also common in heritable connective tissue diseases and is often present in hypermobile patients.

References:

Done JD, et al. Role of mast cells in male chronic pelvic pain. Journal of Urology 2012: 187, 1473-1482.

Roman K, et al. Tryptase-PAR2 axis in experimental autoimmune prostatitis, a model for chronic pelvic pain syndrome. Pain 2014: 155 (7), 1328-1338.

Cohen D, et al. The role of pelvic floor muscles in male sexual dysfunction and pelvic pain. Sex Med Rev 2016; 4, 53-62.

Murphy SF, et al. IL17 mediates pelvic pain in experimental autoimmune prostatitis (EAP). PLoS ONE 2015, 10(5) : e0125623.

 

Hypermobility Type Ehlers Danlos Syndrome and Autonomic Dysfunction (Part One)

Ehlers Danlos Syndrome (EDS) is a heritable connective tissue disease with six major subtypes. EDS occurs in approximately 1/5000 births.  Classical EDS (cEDS) and hypermobility type EDS (HEDS or ht-EDS) are the most common forms, with approximately 90% of patients having one of these types.  Vascular EDS (vEDS) affects about 5% of EDS patients.  The remaining types are rare. Generally, EDS patients demonstrate hypermobility of joints, excessive stretchiness of the skin (hyperextensibility) and fragility of soft tissues.

Ehlers Danlos is diagnosed by clinical evaluation and diagnostic testing.  Mutations affecting structure of collagen, a key component of connective tissue, have been identified for cEDS and vEDS.  For hypermobility type EDS, no consistent genetic anomality has been found.  As a result, diagnosis of this subtype relies upon patient history and clinical examination.

The Beighton scale is a nine point scale for evaluating hypermobility.  One point is granted for each: elbow hyperextended more than 10°, knee hyperextended more than 10°, thumb that can be touched to the forearm, and fifth finger that can be passively bent back more than 90°.  One further point is granted for being able to place the palms flat on the floor with knees fully extended.  A score of 5 points or more is suggestive of joint hypermobility, a major criterion for diagnosis of HEDS.

In addition to an appropriate Beighton score, soft skin with normal or slight hyperextensibility and absence of significant soft tissue abnormalities are also important for HEDS diagnosis.  Excessive skin hyperextensibility and serious fragility of connective tissue could be indicative of other forms of EDS.

Hypermobility type EDS was regarded for many years as a benign laxity of the joints.  In recent years, this position has been debunked, though this belief still persists for many medical providers. Hypermobility and musculoskeletal pain were previously recognized as the dominant manifestations, but we now know that HEDS can cause cardiovascular, gastrointestinal, genitourinary and neurologic symptoms, among others.  In fact, the aspects of this disease that aren’t musculoskeletal are the most disabling and are correlated with lower quality of life

Symptoms arising from dysfunction of the autonomic nervous system have serious impact on quality of life as demonstrated in a number of conditions, including chronic fatigue syndrome and fibromyalgia.  Autonomic dysfunction can be assessed with an Autonomic Symptom Profile (ASP), a questionnaire of 169 questions that evaluates symptoms in eight broad categories: orthostatic (upright posture), secretomotor (secretion of substances by glands), urinary, GI, pupillomotor (movement of the pupil), vasomotor (changing diameter of blood vessels), reflex syncope (dysfunction of blood pressure and heart rate) and sleep function. These functions are all controlled by the autonomic nervous system.

References:

de Wandele I, et al. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Seminars in Arthritis and Rheumatism 2014, 44: 93-100.

de Wandele I, et al. Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: A comparative study with two other EDS types, fibromyalgia, and healthy controls. Seminars in Arthritis and Rheumatism 2014, 44: 353-361.

Wallman D, et al. Ehlers-Danlos Syndrome and Postural Tachycardia Syndrome: A relationship study. Journal of Neurological Sciences 2014, 340: 99-102.

Mast cells in nerve pain

Mast cells are heavily involved in the generation and sensation of pain. The role of mast cells in neurogenic pain (also called nerve pain or neuropathy) is well established and is responsible for a number of painful conditions.

Pain is transmitted like this:

  1. You first feel the pain in nerve endings called nociceptors.
  2. These nerve endings and capillaries in the nearby tissue form a “pain unit” that sends pain signals.
  3. Mast cells are often found close to these nerve endings and capillaries. They release mediators like prostaglandins, histamine and bradykinin.
  4. Nociceptors release mediators like substance P, VIP and CRH, which activate mast cells.
  5. Mast cells then release mediators that increase permeability of the vessels and sensitize the nociceptors. This cycle, in which the nerve endings activate mast cells and the mast cells activate the nerve endings, is called a positive feed back loop. The end result is neurogenic inflammation, or inflammation caused by nerves.

Mast cells can communicate with nerve endings in a number of ways. The first way is by releasing mediators, which may bind to receptors on the nerve cells. A second way is by mast cells sticking to nerve cells through molecules like CADM-1 and N-cadherin; they are able to send signals when their membranes are touching. A third way is by the nerve cells ingesting mediators released by mast cells. These mediators are then transported to other nerve cells, where it can affect which genes are turned on and used.

Mast cells also draw other immune cells to the site of inflammation, like neutrophils and T cells. These cells also release mediators that increase pain, forming another positive feedback loop. The result is that inflammation can spread beyond the initial site of pain, causing a secondary, larger pain response. Hyperalgesia is an exaggerated pain response that is more severe than expected based upon the injury. Mast cells are thought to be directly involved in hyperalgesia and histamine is thought to cause this heightened pain sensation.

Chronic pain has been associated with mast cell degranulation. Degranulation close to colonic nerves is correlated with abdominal pain in IBS patients. Tryptase and histamine can also activate enteric nerves, causing the nerves to be oversensitive. Esophageal pain is also a function of mast cell degranulation.

The specific mechanism of bladder pain due to interstitial cystitis is not clear. However, mast cells are often elevated in IC patients, and contribute to inflammation. It is thought that activation of bladder nerves causes release of substance P by local nerve endings, which activates mast cells.

Overly sensitive and painful skin is sometimes a function of mast cells as well. A significant increase in mast cells has been found in the dermis of fibromyalgia patients. Chronic granulomatous inflammation of the skin causing pain has also been found to be from degranulation of mast cells.

 

References:

Heron, Anne, Dubayle, David. 2013. A focus on mast cells and pain. Journal of Neuroimmunology 264 (2013) 1–7.

Parada, C.A., Tambeli, C.H., Cunha, F.Q., Ferreira, S.H., 2001. The major role of peripheral release of histamine and 5-hydroxytryptamine in formalin-induced nociception. Neuroscience 102, 937–944.

Theoharides, T.C., Kempuraj, D., Sant, G.R., 2001. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology 57, 47–55.

Theoharides, T.C., Donelan, J., Kandere-Grzybowska, K., Konstantinidou, A., 2005. The role of mast cells in migraine pathophysiology. Brain Res. Brain Res. Rev. 49, 65–76.

Gao, G., Ouyang, A., Kaufman, M.P., Yu, S., 2011. ERK1/2 signaling pathway in mast cell activation-induced sensitization of esophageal nodose C-fiber neurons. Dis. Esophagus 24, 194–203.

MCAS: Neurologic and psychiatric symptoms

The neuropsychiatric symptoms associated with MCAS are numerous and are results of the chemicals released by mast cells.

Headaches are a very common complaint. They can sometimes be managed with typical remedies (Excedrin, Tylenol) and antihistamine treatment often helps with this symptom quickly. However, in some patients, headaches can be disabling. Diagnosis of migraine is not unusual, with mast cell degranulation having been tied previously to migraines.

Dizziness, lightheadedness, weakness, vertigo, and the feeling of being about to faint are all typical in MCAS, though true fainting spells are less common than in mastocytosis. These symptoms often cause many MCAS patients to be diagnosed with dysautonomia or POTS.

MCAS patients often experience increased activation of sensory and motor nerves. This manifests as generic neurologic symptoms, sometimes several at once, like tingling, numbness, paresthesia and tics. Tics generally do not spread from the place they initially present. Paresthesias seem to progress for a period of time, then wane and disappear. Extremities are most commonly affected.

EMG and nerve conduction studies are typically normal or abnormal in a way that is not diagnostic. These tests sometimes reflect a possibility of chronic inflammatory demyelinating polyneuropathy (CIDP.) These patients also sometimes are positive for monoclonal gammopathy of unknown significance (MGUS), a blood marker that has been tied to multiple myeloma. However, in these patients, the MGUS is believed to be an effect of the MCAS.

Another subset of patients are diagnosed with subacute combined degeneration (SCD), a deterioration of the spinal cord associated with B12 deficiency. They are sometimes treated for pernicious anemia despite lack of hematologic support for this diagnosis.

Prostaglandin D2 is a known effector of nerve damage and has been blamed for many of the neurologic symptoms seen in MCAS. Astrogliosis, abnormal proliferation of astrocytes (nerve cells in the brain), and demyelination (loss of the insulating cover for nerves that allows the body to send signals) are markers of neurodegeneration. These factors cause scarring and inhibit nerve repair mechanisms. PGD2 is made by an enzyme called hematopoietic PGD synthase. In mice that don’t make this enzyme, these kinds of neuroinflammation are suppressed. Treatment of normal mice with an inhibitor of this enzyme (HQL-72) also decreases these actions. This indicates that PGD2 is critical in causing neuroinflammation including demyelination. PGD2 also activates pain receptors strongly, causing sometimes profound neurologic pain.

PGD2 is also the most potent somnagen known, meaning that it induces sleep more strongly than any other molecule. MCAS patients report inordinately deep sleep, “mast cell coma.” This is likely due to excessive PGD2. Conversely, some MCAS patients also have insomnia, from excessive histamine.

I have written at length before about cognitive and psychiatric manifestations of mastocytosis, which are the same as in MCAS. Cognitive and mood disturbances are all kinds are reported. Brain fog, including short term memory troubles and word finding problems, is the most common symptom. Irritability, anger, depression, bipolar affective disorder, ADD, anxiety, panic disorders and even sometimes frank psychosis can present. Such symptoms in mastocytosis patients were referred to as mixed organic brain syndrome, a term coined in 1986. The important aspect of these symptoms in MCAS is that they are caused by mast cell activation. As such, they are most effectively treated by managing mast cell release symptoms. Some patients do find relief in some psychiatric medications, but the psychiatrist should be aware that these symptoms are part of mast cell pathology.

Additionally, PTSD is not rare in MCAS patients. This is most often due to the trauma from negative interactions with the medical industry.

Autism is significantly increased in patients with mastocytosis. Similar findings are beginning to surface with MCAS patients. Interesting, most autism spectrum disorder patients have food intolerance and general allergic symptoms. A future post will discuss this in more detail.

References:

Afrin, Lawrence B. Presentation, diagnosis and management of mast cell activation syndrome. 2013. Mast cells.

Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J. Hematol. Oncol.2011;4:10-17.

Ikuko Mohri, Masako Taniike, Hidetoshi Taniguchi, Takahisa Kanekiyo, Kosuke Aritake, Takashi Inui, Noriko Fukumoto, Naomi Eguchi, Atsuko Kushi, Hitoshi. Prostaglandin D2-Mediated Microglia/Astrocyte Interaction Enhances Astrogliosis and Demyelination in twitcher. The Journal of Neuroscience, April 19, 2006 • 26(16):4383– 4393.

Rogers MP, et al. Mixed organic brain syndrome as a manifestation of systemic mastocytosis. Psychosom Med. 1986 Jul-Aug;48(6):437-47.

 

Neurologic symptoms of mast cell disease

Mast cells are known to closely associate with nerve endings and to be important in neurotransmission.  This can translate into a variety of neurologic symptoms.
In 2011, a retrospective study on the neurologic symptoms of mast cell patients (171 SM patients, 52 CM patients, all adult) was published.  The following is a summary of the results.
Syncope (fainting) is a well-defined complication of mastocytosis, reported here in 14.3% of patients .  In these patients, evaluation revealed that the likelihood of epileptic involvement was likely low.  About 2/3 of patients who had fainting episodes also had loose stool, cramping, nausea, sweating and flushing accompanying the episode.  Prostaglandin D2 and histamine are known to cause low blood pressure and fainting in addition to GI symptoms.  Aspirin is thought to protect against acute vascular collapse and fainting, and sees use in tolerant patients for these purposes.   
16.6% of mastocytosis patients complained of back pain.  In all but one patient, the cause was determined to be multifocal compression fractures throughout the spine, including thoracic region.  Vertebroplasty, a procedure in which special bone cement is applied to the fractured vertebrae, has been suggested for symptom relief of these patients.  One patient was found to have back pain due to dense mast cell infiltration of the vertebrae.  In this patient, radiation therapy provided symptom relief.
35% of patients reported headaches.  Several of these patients met the criteria for migraines.  Mast cells have been implicated repeatedly in migraine pathology, and mastocytosis patients are more likely to suffer from them than the general population.  In response to mast cell degranulation, reactive changes have been noted in trigeminal nerve, the structure responsible for sensation in the face and activities like chewing.  Trigeminal neuralgia has been noted in some patients with mast cell disease.
This paper was also the first to find a link between mastocytosis and multiple sclerosis.  Two adults with ISM developed relapsing remitting MS, and a patient with isolated UP developed primary progressive MS.  Mast cells are known to associate with MS lesions, and mast cell activation can be detected in cerebrospinal fluid of MS patients.  This study found an MS frequency of 1.3% among mastocytosis patients, compared to 0.1% in the general population.
Lastly, an association has been found between overall mast cell burden and susceptibility to experimental autoimmune encephalitis (EAE.)
Reference:
Smith, Jonathan H, Butterfield, Joseph H, Pardanini, Animesh, DeLuca, Gabriele, Cutrer, F Michael.  Neurologic symptoms and diagnosis in adults with mast cell disease.  Clinical Neurology and Neurosurgery 113 (2011) 570-574.