manu r. sood - home | the ehlers danlos society sood.pdf“idiopathic” myositis and neuropathies...

Manu R. Sood

Children’s Hospital of Wisconsin

& Medical College of Wisconsin

Milwaukee, WI

Joint hypermobility syndrome (JHS) was first described by Kirk and colleagues in 1967

1980s – phenotypic overlap of JHS with heritable disorders of connective tissue recognized (EDS type III)

Gynecological problems

Chronic pain and dysautonomia

Last decade - association with GI disorders

Review the association of pediatric functional GI and motility disorders with joint hypermobility syndrome (JHS)

Explore possible mechanisms for GI symptoms in JHS

Discuss therapeutic approaches to functional GI and motility disorders

Spontaneous bowel perforation

GI haemorrhage

Hiatus hernia

Intestinal diverticula

Rectal prolapse

0%

10%

20%

30%

40%

50%

60%

70%

80%

IBS FunctionalConstipation

GERD

N=135

Prevalence of JHS 33% ◦ Heartburn

◦ Water brash

◦ Postprandial fullness

Upper and lower GI symptoms increased with increasing severity of JHS phenotype.

•Structural support

•Nourishment to the mucosa

•Rich in immune cells

•Contains cells which help

maintain homeostasis

1950 1960 1970 1980 1990 2000 2013

Abnormal Motor Function

Visceral Hyperalgesia

Brain Gut Interaction

Genetics, Microbial-mucosal, Neuro-immune

Purely Psychosocial Disorders

Pathophysiology of Pain Related

Functional GI Disorders

Fifteen year old with 2 year history of abdominal pain and nausea

Pain worse after eating

Intermittent vomiting

Episodes of dizziness but no fainting

No heartburn or feeling of food getting stuck in the chest

Stomach ulcer Normal stomach

Intrinsic System: ◦ Myenteric plexus

◦ Submucosal plexus

Extrinsic Neural Interactions: ◦ Parasympathetic

Dorsal motor nucleus of vagus

Sacral spinal cord

◦ Sympathetic reflexes

Celiac, superior & inferior mesenteric ganglia

71% pediatric gastroenterologists (n=362) used Rome criteria

Only 45% of the surveyed pediatric gastroenterologists found the Rome criteria useful

The reported prevalence of POTS in joint hypermobility syndrome is 78%

Storage

Breakdown of ingested food

Controlled emptying of food into the small bowel

Volume

Pre

ssure

Satiety

Discomfort

Volume

Pre

ssure

Satiety

Discomfort

Gastric pain perception in children with RAP lower than controls p<0.005 and IBS patients (p<0.01)

Volume of water consumed ◦ Chronic abdominal pain 395 ± 198 ml

◦ Controls 528 ± 257 ml. (p < 0.01)

◦Using a cut off of 275 ml the sensitivity was 33% and specificity 100%

28 patients with dyspepsia and 15 obese subjects

As a group, children with

functional dyspepsia ingested

significantly smaller meal

volume and had slower gastric

emptying time.

Titurbation of Gastric Contents

◦ Solids mechanically disrupted

◦ Empty sizes of only 1-2 mm

◦ Larger non-digestable contents empty during fasting MMC

Gamma

Camera 99mTc in 300 kcal

egg meal

Four hour studies are more reliable

Always use a meal which has been cooked after adding the radioisotope

Also pay attention to the first 60 min (rapid emptying)

Stomach

Chitkara DK, Camilleri MC et al. Journal of Pediatrics 2005

15 adolescent patients

15 young adult controls

Life style changes ◦ Small frequent meals

◦ Low fiber and low fat diet

Prokinetic ?

Cyproheptadine

Visceral hypersensitivity ◦ TCA

◦ Neurontin

POTS and autonomic dysfunction: ◦ Fluid intake

◦ Salt supplements

◦ Fludrocortisone

Target the most bothersome symptom

Article Intervention Outcome

Robins et al, 2005

n=69; 6-16 y

CBT vs. SMC

FU: 1 y

CBT Improvement in pain

Benefit maintained at 1 y FU

Duarte et al, 2006

n=32; 5-13 y

CBT vs. SMC

4 monthly sessions

FU: 4 m

CBT: Improvement in pain scores (86.6% vs.

33.3%)

Hicks et al, 2006

n=47; 9-16 y

CBT: vs. SMC

FU: 3 m

CBT: Improvement in pain scores (72% vs.

14%)

Weydert et al,

2006

N=22; 5-18y

Guided imagery vs

breathing exercises

Four sessions , FU: 3m

Guided Imagery: Greater decrease in pain

and missed activities ( 82% vs. 45%) at 2 m

van Tilburg et al,

2009

n=34; 6-15y

Home based guided

imagery vs. SMC

2 months treatment and

FU: 6m

Guided imagery group: more treatment

responders (63.1% vs. 26.7%).

Levy et al, 2010

n=200; 7-17 y

CBT vs. Educational support

3 session each group

FU: 6m post treatment

CBT: Improvement in pain and GI symptoms and less parental solicitous responses

Almost 80% of children with

pain associated FGIDs improve

with CBT

Digestion and

Absorption of Nutrients

Cleansing when asleep

• Normal

• Extrinsic (autonomic) neuropathy

• Intrinsic (enteric) neuropathy

• Antral postprandial hypomotility

• Intestinal myopathy

• Rumination

• Mechanical obstruction

• Nonspecific conditions

Water perfused AD manometry High resolution AD manometry

UK (n=35)

43%

47%

10% 56%

38%

6%

S. Heneyke, et al. Arch Dis Child 1999;81:21-27

Mousa H, et al. Dig Dis Sci 2002;47:2298

USA (n=85)

“Idiopathic” myositis and neuropathies

Eosinophilic enterocolitis and neuropathy

Systemic lupus erythematosus/ Crohn’s

Autoimmune (ANNA-1)

Mitochondrial diseases (MNGIE)

Deficient Interstitial Cells of Cajal

New drug effects- Perinatal Zidovudine

Viral infections (CMV, EBV, HSV, rotavirus)

Yamazaki-Nakashimada MA, et al. JPGN 2009;48:482

Smith VV, et al. Gastroenterol 1998;114:421 Ruuska TH, et al. Gastroenterol2002;122:1133 Smith VV, Milla PJ. Histopathology 1997;31:112

Eosinophilic myenteric ganglionitis

Mega-mitochondria in ganglion cells

Autoimmune enteric leiomyositis

Malrotation: almost 25% to 28% of CIP patients

After Ladd’s procedure: persistent feeding

intolerance, vomiting & abdominal distension

investigate for CIP

Megacystis and hydronephrosis are present in

41% to 44% of patients with CIP

Developmental delay 40%

Autonomic dysfunction 22%

S. Heneyke, et al. Arch Dis Child 1999;81:21-27

Mousa H, et al Dig Dis Sci 2002;47:2298

200 patients and 100 controls

JHS - 32% patients and 14% controls

JHS group ◦ Constipation score, abdominal pain, use of

laxatives and need for manual assistance were significantly higher

JHS group more likely to have incomplete rectal clearance and anorectal anatomical problems

Dr. Nichopoulos own words “I realized during the autopsy how much more severe Elvis’s discomfort must have been than I had realized”.

Thick muscle

Better propulsive force

Less stool load

Thin muscle

Poor propulsive force

More stool load

Stool expulsion

Slow transit

Gutierrez, et al J Pediatr Gastroenterol Nutr;2002

Cook BJ, et al. J Pediatr Surg;2005

Benninga MA, et al. Arch Dis Child;2004

Chitkara DK, et al. Am J Gastroenterol 2004

n=69 n=22 n=19

Children with functional constipation

have increased rectal compliance

compared to children who had

recovered from functional constipation W.P. Voskuijl WP, et al. J Pediatr 2006

Baseline (n=101) rectal compliance ◦ Normal in 36% ◦ Moderately increased in 40% ◦ Severely increased in 24%

After 1 year, treatment success was similar between groups ◦ 42% normal ◦ 41% moderately increased ◦ 40% with severely increased compliance

Van den Berg MM, et al. Gastroenterology 2009

Ascending

Colon

Trans. Colon

Trans. Colon

Descending

Colon

Sig. colon

Rectum

Anal canal

HAPC

Rectal propagating

contractions

Anal canal

High Resolution Colon Manometry

Almost 70% of patients report successful outcome

Absence of HAPCs in the entire colon associated with poor outcome

Almost 40% able to discontinue antegrade enemas within 2 yrs.

Youssef N, et al. J Pediatr Gastroenterol Nutr. 2002

van den Berg MM, et al. J Pediatr Surg. 2006

13 females ◦ Median age at onset of symptoms

15.2 yrs. (range 10-18yrs.) ◦ Median duration of laxative therapy

7 yrs. (range, 1–17 yrs.)

Slow colon transit in 7 patients Follow up after sacral

neuromodulation ◦ 6 months (n=13) ◦ 1 year (n=5)

Complications: ◦ Pain at the site of implant ◦ Lead problem requiring revision

Functional GI and motility problems are common in patients with JHS and EDS

Altered biomechanics and sensory bowel abnormalities contribute to symptom generation

Good diagnostic test are not available

Referral to a specialist center with a multidisciplinary team approach should be considered

Gisela Chelimsky, MD

Thomas Chelimsky, MD

Julie Banda, PNP

B U K Li, MD

Adrian Miranda, MD

Katja Kovacic, MD