Medically Unexplained Symptoms

1. Medically Unexplained Symptoms Mark Feldman, MD July 5, 2006

2. Case 1 • 36 year old woman presented with atypical facial pain admitted to Teaching Service. Physical examination was normal. • Past history: depression, anxiety and Mollaret’s meningitis. • Meds: Trazodone, venlafaxine, chlorazepate; valacyclovir • Started on gabapentin (Neurontin) with no pain relief. • Switched to carbamazepine (Tegretol) with no pain relief. • A few weeks later, she developed a severe generalized pruritic maculopapular rash, “granulomatous” hepatitis, and eosinophilia (35%), treated with prednisone and hydroxyzine. She then developed CNS vasculitis with multiple strokes (carbamazepine hypersensitivity syndrome [CHS] with CNS vasculitis).

3. Case 2 • 53 year old woman referred for chronic upper and lower abdominal pain and constipation. • Past history of anxiety, depression, stress, perineal pain, fibro-myalgia, nonulcer dyspepsia, and hysterectomy/oophorectomy. • Recent flare of pain led to laparoscopic appendectomy, with no pain relief (and no abnormality of the appendix on path exam). • Common bile duct was slightly dilated (10 mm) on ultrasound [history of cholecystectomy 20 years ago for upper abdominal pain]. GI was consulted and an ERCP was attempted, complicated by acute pancreatitis requiring hospitalization. • Physical exam and lab studies at this time were normal. • Abdominal pain and constipation improved with the 5-HT4 agonist tegaserod (Zelnorm). Her dyspepsia did not improve and was treated with a PPI with minimal relief. She is being seen by at least 3 gastroenterologists currently.

4. Case 3 • 22 year old woman (daughter of a physician) referred because of flushing, abdominal cramps, and loose stools after eating. She is unable to attend school or work due to her GI symptoms. • Negative or normal: colonoscopy X2; stool fat; urine 5-HIAA, sprue panel, EGD, CT, octreoscan, EUS, etc. • Past medical history of obesity, “PCOS” [with normal ovarian sonogram], asthma, multiple food sensitivities/allergies, chronic headaches, myalgia and arthralgia compatible with FM, multiple knee surgeries, possible Sjögren’s syndrome. Taking 23 medications from numerous specialists such as an allergist/pulmonologist and endocrinologist, including prednisone and octreotide. • Exam (with parents present): morbidly obese and Cushingoid with buffalo hump and hundreds of red and purple striae, but otherwise well-appearing. Exam was otherwise normal and laboratory studies were all normal.

5. Summary of Cases

6. Working definitions • Symptom: a patient’s subjective experience of a change in his/her body • Disease: an objective, observable abnormality in the body When we can find no objective change to explain the patient’s subjective experience, we term the symptoms “medically unexplained” or “functional”.

7. Synonyms for today’s topic • Medically unexplained symptoms • Somatization • Somatoform disorder • Functional Somatic Syndromes

8. Gastroenterology: Gynecology: Rheumatology: Cardiology: Infectious Disease: Neurology: Dentistry: ENT: Allergy: IBS, nonulcer dyspepsia PMS, chronic pelvic pain Fibromyalgia Atypical or non-cardiac CP Chronic fatigue syndrome (CFS) Tension headache TMJ syndrome / atypical facial pain Globus syndrome Multiple chemical sensitivity Functional somatic syndromes, classified by subspecialty * * Adapted from Wessely S, Nimnuan C, Sharpe M. Lancet 354: 936-9, 1999

9. Characteristics of the various Functional Somatic Syndromes • They are extremely common. • They are frequently persistent (i.e., chronic). • Conventional medical therapy is fairly ineffective. • They are associated with: • Considerable distress (IBS > IBD in inpatients) • Considerable disability (CFS > CHF in outpatients) • Unnecessary expenditures of medical revenues • Unnecessary exposure to medical risks • Case 1. Anticonvulsant drugs • Case 2. ERCP • Case 3. Glucocorticoids

10. Frequency of Functional Somatic Syndromes • Primary care consultations (UK): 20% • New referral as medical outpatients (UK): 35% • Medical outpatient visits (Denmark): 25%

11. Potential Splitters: Specialists Specialty Societies Support/Help Groups local chapters Internet sites Researchers Potential Lumpers: Primary care providers Epidemiologists Researchers Mental health professionals Enlightened specialists Functional Somatic Syndromes: One or Many ?

12. A case for Lumping Argument 1 There is a great deal of overlap in case definitions of specific syndromes. Of 12 “specific” syndromes analyzed by Wessely et al, the definition of the syndrome included: • Bloating/feeling of abdominal distention in 8 • Headache in 8 • Fatigue in 6 • Abdominal pain features in 6

13. Pain (“tender points”) Fatigue Sleep disturbances Depression Anxiety Brain fog (“fibro fog”) Migraine headaches Abdominal pain, bloating, alternating diarrhea and constipation (IBS) TMJ disorder Skin color changes Tingling limbs Restless legs syndrome Fibromylagia (Arthritis Foundation)

14. Primary Symptoms (n=8): Cognitive dysfunction Post-exertion malaise afterphysical or mental exertion Unrefreshing sleep Joint pain Persistent muscle pain New headaches Tender cervical/axillary lymph nodes Sore throat Other common symptoms: Irritable bowel syndrome Abdominal pain, diarrhea Nausea, bloating Chills and night sweats Brain fog Chest pain Shortness of breath/chronic cough Multiple food/chemical allergies/sensitivities Psychological problems Depression, anxiety, mood swings, irritability Jaw (facial) pain Weight loss or gain Chronic fatigue syndrome (CDC)

15. Fatigue Difficulty concentrating Depressed mood Memory loss Weakness Headaches Heat intolerance Arthralgia Numerous GI symptoms Respiratory/mucosal irritation Multiple Chemical Sensitivity Syndrome. Common Symptoms Magill and Suruda. American Family Physician, Sept. 1, 1996.

16. A case for Lumping Argument 2 Patients with one functional syndrome frequently meet diagnostic criteria for other syndromes (if queried!). Wessely et al: • CFS: linked to/overlaps with FM, tension headache, multiple chemical sensitivity, food allergy, PMS, and IBS. • IBS: linked to NUD, CFS, hyperventilation, FM, tension headache, atypical facial pain, non-cardiac CP, chronic pelvic pain. and PMS.

17. A case for Lumping Argument 3 Patients with “different” symptoms (functional syndromes) share non-symptom features: • Gender: female predominance of non-gynecologic FSSs, such as IBS, CFS, TMJ dysfunction, atypical facial pain, globus syndrome, tension headaches. • Association of FFSs with emotional disorders: correlated with current and past anxiety and depression. Examples: IBS, multiple chemical sensitivity, CFS • Pathophysiology: Little known, but FSSs may share a common pathophysiology (altered functioning of the CNS) rather than be caused by disorders in specific organ systems • IBS: Colon  CNS • NUD/Bloating: Stomach  CNS • FM and CFS: Muscle  CNS • Facial pain: TMJ, etc.  CNS } ? Role of 5-HT neurons

18. A case for Lumping Argument 3, cont’d • History of childhood mistreatment and/or abuse, especially sexual abuse: pelvic pain, PMS, IBS, tension headache, FM, CFS • Difficulties in the doctor-patient relationship: • Unsatisfactory for the doctor • Unsatisfactory for the patient • headache, non-cardiac chest pain, FM, CFS

19. A case for Lumping Argument 4 All functional syndromes respond to similar therapies. • General approaches: • Take patients’ complaints seriously. • Explain the physiology of the symptoms. • Limit investigations. • Emphasize rehabilitation at the expense of cure. • Antidepressant drugs (tricyclic, SSRI: off label): • Accepted for PMS, atypical facial pain, non-cardiac chest pain • Role in FM, CFS, and IBS less clear, but evolving • Psychological therapies (e.g., cognitive behavioral therapy): • Effective in CFS, PMS, IBS, and in nearly all pain syndromes

20. Rome III. Psychosocial aspects of the functional GI disorders. Levy et al. Gastroenterology 130: 1447-58, 2006. The committee reached consensus in finding considerable evidence supporting the association between psychological distress, childhood trauma and recent environmental stress, and several of the FGIDs but noted that this association is not specific to FGIDs. … there is now increasing evidence that a number of psychological treatments and antidepressants are helpful in reducing symptoms and other consequences of the FGIDs in children and adults.

21. Multiple Chemical Sensitivity (MCS) Syndrome Several theories have been advanced to explain the cause of MCS, including allergy, toxic effects and neurobiologic sensitization. There is insufficient scientific evidence to confirm a relationship between any of these possible causes and symptoms. Patients with MCS have high rates of depression, anxiety and somatoform disorders, but it is unclear if a causal relationship or merely an association exists between MCS and psychiatric problems. Physicians should compassionately evaluate and care for patients who have this distressing condition, while avoiding the use of unproven, expensive or potentially harmful tests and treatments. The first goal of management is to establish an effective physician-patient relationship. The patient's efforts to return to work and to a normal social life should be encouraged and supported. Magill and Suruda. Amer Fam Physician, September, 1998

22. Functional Somatic Syndromes: New or Old Concept ? • Psychosomatic Syndromes • Psychosomatic Affections • Multiple Visceral Neuroses • Syndrome Shift

23. Implications • For sub-specialists: • Elicit symptoms outside of your area of specialty (look at the big picture) • Ask about childhood/sexual abuse • Minimize excessive testing if symptoms fit a functional disorder • Consider more general and safer therapies • For primary care physicians: • Look at the company your patient’s symptoms keep • Minimize referrals to sub-specialists if patient has evidence of multiple functional somatic syndromes • Seek co-existing anxiety and/or depression and treat accordingly • Ask about childhood/sexual abuse • Be willing to consider off-label antidepressants for symptoms • Be prepared to refer difficult/refractory cases to a mental health professional