The Role of Cannabinoids in the Treatment of Cerebral Aneurysm

Cerebral Aneuryism

An aneurysm is a weak area in the wall of a blood vessel that causes the blood vessel to bulge or balloon out.  When an aneurysm occurs in a blood vessel of the brain,  it is a cerebral aneurysm.

Causes

Aneurysms in the brain occur when there is a weakened area in the wall of a blood vessel.  An aneurysm may be present from birth (congenital) or it may develop later in life, such as after a blood vessel is injured.

There are many different types of aneurysms.  A berry aneurysm can vary in size from a few millimeters to over a centimeter.  Giant berry aneurysms can reach well over 2 centimeters.  These are more common in adults.  Multiple berry aneurysms are inherited more often than other types of aneurysms.

Other types of cerebral aneurysm involve widening of an entire blood vessel, or they may appear as a "ballooning out" of part of a blood vessel.  Such aneurysms can occur in any blood vessel that supplies the brain.  Atherosclerosis, trauma, and infection, which can injure the blood vessel wall, can cause cerebral aneurysms.

About five percent  of the population has some type of aneurysm in the brain, but only a small number of these aneurysms cause symptoms or rupture.  Risk factors include a family history of cerebral aneurysms, and certain medical problems such as polycystic kidney disease, co-arctation of the aorta, and high blood pressure.

A common location of cerebral aneurysms is on the arteries at the base of the brain, known as the Circle of Willis.   Approximately eighty five percent  of cerebral aneurysms develop in the anterior part of the Circle of Willis,  and involve the internal carotid arteries and their major branches that supply the anterior and middle sections of the brain.

Cerebral aneurysms are classified by size and shape. Small aneurysms have a diameter of less than (15 mm). Larger aneurysms include those classified as large (15 to 25 mm),  giant (25 to 50 mm),  and super giant (over 50 mm). Saccular aneurysms are those with a saccular outpouching and are the least common form of cerebral aneurysm.  Berry aneurysms are saccular aneurysms with necks or stems resembling a berry. Fusiform aneurysms are aneurysms without stems.

Symptoms

A person may have an aneurysm without having any symptoms.  This kind of aneurysm may be found when an MRI or CT scan of the brain is done for another reason.

A cerebral aneurysm may begin to "leak" a small amount of blood.  This may cause a severe headache that a patient may describe as "the worst headache of my life."  Another phrase used to describe this is a sentinel headache.  This means the headache could be a warning sign of a rupture days or weeks after the headache first happens.

Symptoms may also occur if the aneurysm pushes on nearby structures in the brain or breaks open (ruptures) and causes bleeding into the brain.

Symptoms depend on the location of the aneurysm, whether it breaks open, and what part of the brain it is pushing on, but may include:

  1. Double vision
  2. Loss of vision
  3. Headaches
  4. Eye pain
  5. Neck pain
  6. Stiff neck
  7. A sudden, severe headache is one symptom of an aneurysm that has ruptured.  Other symptoms of an aneurysm rupture may include:
  8. Confusion, lethargy, sleepiness, or stupor
  9. Eyelid drooping
  10. Headaches with nausea or vomiting
  11. Muscle weakness or difficulty moving any part of the body
  12. Numbness or decreased sensation in any part of the body
  13. Seizures
  14. Speech impairment
  15. Stiff neck (occasionally)
  16. Vision changes (double vision, loss of vision)

NOTE:  A ruptured aneurysm is a medical emergency.

Most cerebral aneurysms go unnoticed until they rupture or are detected by brain imaging.

What are the dangers?

Aneurysms may burst and bleed into the brain, causing serious complications,  including hemorrhagic stroke, permanent nerve damage, or death.  Once it has burst, the aneurysm may burst again and bleed into the brain, and additional aneurysms may occur.  More commonly, rupture may cause a subarachnoid hemorrhage — bleeding into the space between the skull bone and the brain.  A delayed but serious complication of subarachnoid hemorrhage is hydrocephalus, in which the excessive buildup of cerebrospinal fluid in the skull dilates fluid pathways called ventricles that can swell and press on the brain tissue.  Another delayed postrupture complication is vasospasm, in which other blood vessels in the brain contract and limit blood flow to vital areas of the brain.  This reduced blood flow can cause stroke or tissue damage.

How are cerebral aneurysms treated?

Not all cerebral aneurysms burst.  Some people with very small aneurysms may be monitored to detect any growth or onset of symptoms and to ensure aggressive treatment of coexisting medical problems and risk factors.  Each case is unique, and considerations for treating an unruptured aneurysm include the type, size, and location of the aneurysm; risk of rupture; the individual’s age, health, and personal and family medical history; and risk of treatment.

Two surgical options are available for treating cerebral aneurysms, both of which carry some risk to the individual (such as possible damage to other blood vessels, the potential for aneurysm recurrence and re-bleeding, and the risk of post-operative stroke).

Microvascular clipping involves cutting off the flow of blood to the aneurysm.  Under anesthesia, a section of the skull is removed and the aneurysm is located.  The neurosurgeon uses a microscope to isolate the blood vessel that feeds the aneurysm and places a small, metal, clothespin-like clip on the aneurysm’s neck, halting its blood supply.  The clip remains in the person and prevents the risk of future bleeding.  The piece of the skull is then replaced and the scalp is closed.  Clipping has been highly effective, depending on the location, shape, and size of the aneurysm.  In general, aneurysms that are completely clipped surgically do not return.

A related procedure is an occlusion, in which the surgeon clamps off (occludes) the entire artery that leads to the aneurysm.  This procedure is performed when the aneurysm has damaged the artery.  An occlusion is sometimes accompanied by a bypass, in which a small blood vessel is surgically grafted to the brain artery, rerouting the flow of blood away from the section of the damaged artery.

Endovascular embolization is an alternative to surgery.  Once the individual has been anesthetized, the doctor inserts a hollow plastic tube (a catheter) into an artery (usually in the groin) and threads it, using angiography, through the body to the site of the aneurysm.  Using a guide wire, detachable coils (spirals of platinum wire) or small latex balloons are passed through the catheter and released into the aneurysm.  The coils or balloons fill the aneurysm, block it from circulation, and cause the blood to clot, which effectively destroys the aneurysm.  The procedure may be performed more than once during the person’s lifetime.

People who receive treatment for aneurysm must remain in bed until the bleeding stops.  Underlying conditions, such as high blood pressure, must be treated.  Other treatment for cerebral aneurysm is symptomatic and may include anticonvulsants to prevent seizures and analgesics to treat headache.  Vasospasm can be treated with calcium channel-blocking drugs and sedatives may be ordered if the person is restless.  A shunt may be surgically inserted into a ventricle several months following rupture if the buildup of cerebrospinal fluid is causing harmful pressure on surrounding tissue.  Individuals who have suffered a subarachnoid hemorrhage often need rehabilitative, speech, and occupational therapy to regain lost function and learn to cope with any permanent disability.

Expectations (prognosis)

The outcome varies.  Patients who are in deep comas after an aneurysm rupture generally do not do as well as those with less severe symptoms.

Ruptured cerebral aneurysms are often deadly.  About twenty five percent  of people die within one  day, and another twenty five percent  die within about three  months.   Of those who survive,  about twenty five percent  will have some sort of permanent disability.

Complications

Increased pressure inside the skull
Loss of movement in one or more parts of the body
Loss of sensation of any part of the face or body
Seizures
Stroke
Subarachnoid hemorrhage

Prevention

There are no known ways to prevent a cerebral aneurysm from forming.  People with a diagnosed brain aneurysm should carefully control high blood pressure, stop smoking, and avoid cocaine use or other stimulant drugs.  They should also consult with a doctor about the benefits and risks of taking aspirin or other drugs that thin the blood.  Women should check with their doctors about the use of oral contraceptives.  Controlling risk factors for atherosclerosis may reduce the likelihood of some types of  aneurysms.  If unruptured aneurysms are discovered in time, they can be treated before they cause problems.  Repairing an unruptured cerebral aneurysm is a decision based on many factors (age, general health, size and location).

Cannabinoids and Cerebral Aneurysm

Can cerebral aneurysms be prevented?  Estimation of the hypothermic component in neuroprotection provided by cannabinoids following cerebral ischemia

Abstract
Cannabinoids have neuroprotective potentials, and the expression of endocannabinoids as well as cannabinoid receptors is induced after cerebral ischemia.  They also induce hypothermia by lowering the hypothalamic set point.  We have estimated the significance of such hypothermia in ischemic neuroprotection following systemic administration of WIN 55,212-2, a synthetic cannabinoid receptor agonist. Results showed that WIN 55,212-2 significantly reduced infarct volumes of rats subjected to focal cerebral ischemia (middle cerebral artery occlusion) and significantly decreased ischemic CA1 damage in rats subjected to global cerebral ischemia (two-vessel occlusion).  A significant (approximately 50%) part of this neuroprotection was provided by WIN 55,212-2 induced hypothermia (33.7 ± 1.1 °C/34.9 ± 1.6 °C), because prevention of hypothermia by maintaining body core temperatures between 37.0 and 38.0 °C dissolved the neuroprotective effect into a hypothermic component and an unidentified component. Finally, the ability of WIN 55,212-2 to reduce levels of the proinflammatory cytokine IFNγ in the infarcted hemisphere of rats subjected to focal cerebral ischemia required hypothermia.  For the cannabinoid WIN 55,212-2, we have isolated and directly demonstrated that hypothermia is only part of, although significant, cannabinoid mediated neuroprotection in both global and focal cerebral ischemia.  We conclude that cannabinoids are reliable candidates for drug-induced hypothermia and neuroprotection.  These neuroprotective effects of cannabinoids could provide the basis for potential therapeutic uses of cannabinoids and/or endocannabinoids in stroke.

Therapeutic Hypothermia in Brain Injuries and Related Diseases
Abstract:
Mild or moderate hypothermia is a useful therapeutic method for improving the outcome for patients who have suffered brain injuries including traumatic brain injury and strokes, as well as secondary damages such as neuroinflammation and edema.  The feasibility and safety of therapeutic hypothermia have been evaluated in experimental settings and clinical trials.  Because the efficacy of therapeutic hypothermia, however, is dependent on the cooling method, application time, duration, and strategies, a continuous effort for obtaining optimal standard protocols of controlling temperature and the documentation of hypothermic devices and drugs are required.  Here, we discuss the most recent hypothermia applications in brain injury and related diseases, and review the latest patents in hypothermic devices and cannabinoid-based hypothermia-inducing drugs.  Ultimately, we conclude that a localized hypothermia may overcome the limitations, risks, and side effects of systemic hypothermia, and the combination of local hypothermia and drug treatment may improve clinical benefits.

United States Patent Application
The present invention relates to the use of a cannabinoid receptor agonist for use in induction of hypothermia in a human being for the prophylaxis and treatment of ischemia.
December 2009
Inventor:  Jacob Weber, Denmark

Authors note:
Cannabinoids have been shown to have excellent neuroprotective properties.  It seems logical that they could play a significant role in the treatment of cerebral aneurysm.

References



1. a b Brisman JL, Song JK, Newell DW (August 2006). "Cerebral aneurysms". N Engl J Med 355 (9): 928–39. doi:10.1056/NEJMra052760.PMID 16943405.
2. Appel, Jacob M. Health care hard to recognize, tough to define, Albany Times Union, Nov. 12, 2009
3. Hunt, WE; Hess RM (1968). J Neurosurg 28: 14–20. doi:10.3171/jns.1968.28.1.0014. PMID 5635959.
4. Greenberg, MS (2010). Handbook of Neurosurgery (7th ed). Thieme.
5. Gallo, GL; Rafael Tamargo (October 2006). "Leukocyte-endothelial cell interactions in chronic vasospasm after subarachnoid hemorrhage.".Neurol. Res 28 (7): 750–8. doi:10.1179/016164106X152025. PMID 17164038.
6. http://www.med.unc.edu/neurosurgery/news/germanwala-presents-first-aneurysm-patient-treated-through-nose
7. Raja PV, Huang J, Germanwala AV, Gailloud P, Murphy KP, Tamargo RJ. Microsurgical clipping and endovascular coiling of intracranial aneurysms: A critical review of the literature. Neurosurgery 62: 1187-1202, June 2008
8. Piotin, M; Spelle, L, Mounayer, C, Salles-Rezende, MT, Giansante-Abud, D, Vanzin-Santos, R, Moret, J (May 2007). "Intracranial aneurysms: treatment with bare platinum coils—aneurysm packing, complex coils, and angiographic recurrence.". Radiology 243 (2): 500–8.doi:10.1148/radiol.2431060006. PMID 17293572.
9. Raymond, J; Guilbert, F, Weill, A, Georganos, SA, Juravsky, L, Lambert, A, Lamoureux, J, Chagnon, M, Roy, D (June 2003). "Long-term angiographic recurrences after selective endovascular treatment of aneurysms with detachable coils.". Stroke 34 (6): 1398–1403.doi:10.1161/01.STR.0000073841.88563.E9. PMID 12775880.
10. Piotin M, Spelle L, Mounayer C, Loureiros C, Ghorbani A, Moret J. Intracranial aneurysms coiling with matrix. Immediate results in 152 patients and midterm anatomic follow-up from 115 patients. Stroke November 2008 (e-pub ahead of print)
11. Campi, A; Ramzi N, Molyneaux AJ, Summers, PE, Kerr, RS, Sneade, M, Yarnold, JA, Rischmiller, J, Byrne, JV (May 2007). "Retreatment of ruptured cerebral aneurysms in patients randomized by coiling or clipping in the International Subarachnoid Aneurysm Trial (ISAT).". Stroke 38 (5): 1538–44.doi:10.1161/STROKEAHA.106.466987. PMID 17395870.
12. Mitchell P, Kerr R, Mendelow AD, Molyneux A. Could late rebleeding overturn the superiority of cranial aneurysm coil embolization over clip ligation seen in ISAT? Journal of Neurosurgery 108: 437-442, March 2008
13. Hop, Jeanette; Gabriel Rinkel, Ale Algra, Jan van Gijn (March 1997). "Case-Fatality Rates and Functional Outcome after Subarachnoid Hemorrhage: A Systematic Review.". Stroke 28 (3): 660–4. PMID 11157554.
Ljunggren, B; Sonesson B, Säveland H, Brandt L (1985). "Cognitive impairment and adjustment in patients without neurological deficit after aneurysmal SAH and early operation.". Journal of Neurosurgery 62 (5): 673–9
Bederson JB, Connolly ES Jr, Batjer HH, Dacey RG, Dion JE, Diringer MN, Duldner JE Jr, HarbaughRE, Patel AB, Rosenwasser RH: American Heart Association Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 2009;40:994-1025. [PubMed]
Meyers PM, Schumacher HC, Higashida RT, Barnwell SL, Creager MA, Gupta R, McDougall CG, Pandey DK, Sacks D, Wechsler JR: American Heart Association. Indications for the performance of intracranial endovascular neurointerventional procedures: a scientific statement from the American Heart Associatino Council on Cardiovascular Radiology and Intervention. Stroke Council, council on Cardiovascular Surgery and Anesthesia, Interdisciplinary Council on Peripheral Vascular Disease, and Interdisciplinary Council on Quality of Care and Outcomes Research. Circulation. 2009;119:2235-2249. [PubMed]
Patterson JT, Hanbali F, Franklin RL, Nauta HJW. Neurosurgery. In: Townsend CM, Beauchamp RD, Evers BM, Mattox KL, eds. Sabiston Textbook of Surgery. 18th ed. Philadelphia, Pa: Saunders Elsevier;2007:chap 72.