Curcumin/Turmeric as a Treatment for Patients With Subdural Hematomas Recurrence

Chronic subdural hematomas (cSDH) are extra-axial fluid collections in the cranium that can
result in brain compression and neurological decline. cSDH commonly occurs after traumatic
brain injury (TBI); though, many times there is no history of trauma. The incidence of cSDH
is expected to significantly rise, due to an increasing elderly population worldwide.This is
a common and challenging neurosurgical problem due to their ability to recur requiring
repeated surgical reevacuation. Repeat surgery comes with additional morbidity as well as
rising costs for both patients and hospitals. Operative decompression is the treatment of
choice; however, an effective therapy preventing recurrence of cSDH after surgical
intervention has not yet been found. Our long-term goal is to develop a therapeutic approach
focused on the prevention of cSDH recurrence after initial surgical intervention.

The current literature and our own preliminary data have demonstrated that there is local
elevation of pro-inflammatory chemokines and pro-angiogenic factors within the subdural
hematoma cavity of chronic subdural hematomas that are not found systemically. Interleukin-8
(IL8 or chemokine (C-X-C motif) ligand 8, CXCL8) demonstrates both pro-inflammatory and
pro-angiogenic properties. Curcumin has shown to directly inhibit the production and activity
of CXCL-8 (IL-8) in vitro and in vivo, as well as down regulating the activity of VEGF
(vascular endothelial growth factor) and bFGF (basic fibroblast growth factor). These
combined effects make CC an important anti-inflammatory and antiangiogenic molecule that has
the potential to reduce the recurrence rate of chronic subdural hematomas. The investigators
expect that CC will prevent/reduce persistent hemorrhage within the subdural hematoma cavity,
by blocking IL-8-induced disruption of the blood vessels. Specifically, CC is expected to
preserve blood vessel leakage and accumulation of blood in SDH cavity, by blocking
destructive effect of IL-8 on the vascular endothelial tight junctions.

CC has demonstrated promising results in multiple studies related to brain injury including
intraparenchymal hemorrhage, acute stroke, subarachnoid hemorrhage, and general injury to the
blood-brain-barrier. 6 hours following intracerebral hemorrhage in adult mice, curcumin was
administered in clinically relevant doses of 75-300 mg/kg. After 72 hours, there was a
reduction in hematoma size, decreased vasogenic edema secondary to a less damaged
blood-brain-barrier, decreased inflammatory markers, and overall improved neurological
outcome. After discussing the role of T-lymphocytes in contributing inflammation and
worsening neuronal injury, mouse models were used to demonstrate a suppression of
T-lymphocyte infiltration in the brain after administration of curcumin. There was also a
reduction in cerebral edema and improvement of neurological scores. One study administered
low dose (80mg/day) curcumin to healthy middle-aged adults (40-60 years of age), when
compared to a placebo group. The CC group had lower levels of plasma triglyceride, salivary
amylase levels, plasma beta amyloid protein concentrations (protein responsible for
Alzheimer's disease and other forms of intracerebral hemorrhage), and other beneficial health
effects.

It was recently detected that combining CC with piperine (black pepper extract, also known as
peperine or BioPerine), a known inhibitor of hepatic and intestinal glucuronidation, enhances
the serum concentration, extent of absorption and bioavailability of CC in both rats and
humans. Therefore, CC supplement is now used in combination with the black pepper extract.
The average amount of pepper consumed by a person during a day in the United States is 359
mg, which translates to 18-32 mg of piperine a day. Furthermore, rat trials show a daily
intake of 5 to 20 times the average daily dose of humans produced no clinical symptoms.
Studies on acute, subacute, and chronic piperine toxicity show no abnormalities or clinical
symptomatology, or significant blood chemistry data in laboratory animals. Black pepper
extract has a high degree of safety being used nutritionally. The amount of piperine that is
formulated in the curcumin capsules is several thousand times less than the LD50 (lethal dose
50) established in mice and rats. Our capsule contains 270 mg of pure curcuminoids (curcumin)
and 3mg of black pepper extract. The recommended serving size is 3 capsules a day. Therefore,
the patients will receive 810mg of pure curcumin and 9mg of black pepper extract (peperine)
per day, which is less than the average amount of pepper consumed by a person daily in the
United States.

This is a double-blinded, randomized placebo-controlled pilot study. A total of 48 subjects
will be recruited in this study. 24 patients will receive placebo pills, and 24 will receive
Curcumin (CC) pills. Patients who have symptomatic unilateral chronic subdural hematomas,
with no acute component and do not meet the exclusion criteria, will be evaluated. At the
time of consent for evacuation of the subdural hematoma, patients will also be consented for
this trial by the research team. Participants will be instructed that they will be randomized
to either the placebo group or the curcumin group. Participants will take one capsule three
times a day for a maximum of 60 days. Participants will undergo standard postoperative care
in regard to imaging and clinical follow-up. Patients will begin taking placebo or CC within
24 hours post-operatively and able to take oral medication. It will then be continued three
times a day (TID).

This is a single center study that will take place at the University of New Mexico Hospital
(UNMH). New patients admitted directly to the UNM Neurosciences Intensive Care Unit (NSICU)
as a transfer from an outside hospital as well as patients admitted directly through the UNM
(University of New Mexico) Emergency Department (ED), with subdural hematomas will be
identified and recruited as potential subjects. All surgical operations will take place in
the main operating room (OR) at UNMH. The perioperative care of the enrolled patients, as
well as the non-surgically managed patients will take place both in the NSICU as well as the
Neurosurgical step-down unit. Once patients have been discharged from the hospital, all
follow-up appointments will take place in the Clinical Neurosciences Center located adjacent
to UNMH. Patients will follow-up in the subdural clinic, staffed by Dr. Howard Yonas,
Principal Investigator.

Inclusion Criteria:

1. Chronic subdural hematoma (cSDH)

2. Age of 18 years old or older

3. Unilateral cSDH with no other intracranial injuries

o Membranes with minimal hemorrhage may be included but no clear acute component
should be evident

4. Subdural volume less than 115cc

5. MARWALDER GRADING SCALE Score of 0-2

6. Patient or patient's power of attorney (POA) is available to sign consent

7. Patient undergoes surgical evacuation of cSDH-

Exclusion Criteria:

1. Age less than 18 years old

2. Bilateral subdural hematomas

3. Subdural volume less than 115cc

4. Acute subdural hematoma

5. Patient does not undergo surgical evacuation

6. Other evidence of intracranial injury (i.e. epidural hematoma, intraparenchymal
hemorrhage, skull fractures, subarachnoid hemorrhage, hydrocephalus)

7. Patient's family not available for consent and requires emergent surgical evacuation

8. Previous intracranial surgery

9. Recent head trauma (less than1 week)

10. Use of anti-coagulation (i.e. Coumadin, Heparin, Apixaban, and Rivaroxaban) or
antiplatelets (Plavix) drugs, with the exception of Aspirin

11. Known coagulopathy disorders

12. Positive urine or serum pregnancy test in pre-menopausal female subjects, without a
documented history of surgical sterilization; or currently breastfeeding (Since the
nuclear group in an older population, the pregnancy test will be made in exceptional
cases).

13. Allergy to curcumin or turmeric.

14. Allergy to black pepper

15. Markwalder Grading Scale Score: 3-4

16. Baseline dementia (for more than 6 months). Adult who cognitively impaired for more
than 6 months will be excluded from the study, since this impairment might be due to
other reasons than cSDH, such as dementia or cognitive impairment.