Ataxia in the Stroke Patient Kelli Kulpa BSN

Ataxia in the Stroke Patient Kelli Kulpa BSN, RN Alverno College MSN Student Neurosciences Department Froedtert Hospital

Objectives • Describe pathophysiology of cerebellum as it relates to smooth muscle movements • Describe how ischemia to cerebellum causes ataxia in stroke patient • Identify presence of ataxia in stroke patient • Identify appropriate nursing interventions and outcomes

TOPICS TO REVIEW STROKE CEREBELLUM ATAXIA NIH STROKE SCALE CARE OF THE PATIENT WITH ATAXIA

Stroke • “Syndrome of acute focal neurologic deficit from a vascular disorder that injures brain tissue” Porth (2005, p. 1245) • US leading cause of mortality & morbidity • About 700, 000 Americans afflicted with stroke • Many survivors left with some degree of deficit (Porth, 2005) Image from Microsoft Clipart

Risk Factors for Stroke • Controllable • • Hypertension (HTN) Atrial Fibrillation High Cholesterol Diabetes Tobacco Use & Smoking Alcohol Use Physical Inactivity Obesity (National Stoke Association, 2009) Image from Microsoft Clipart • Uncontrollable • • Age Race Gender Family History Previous Stroke or TIA Fibromuscular Dysplasia Patent Foramen Ovale

Uncontrollable Risk Factor • AGE: • Risk of stroke increases with age • After age 55, risk doubles for every decade that passes • Increased prevalence of controllable risk factors as age increases • Hypertension • High Cholesterol • Diabetes (National Stoke Association, 2009) Image from Microsoft Clipart • RACE: AFRICANAMERICAN • Most impacted race in US • Twice as likely to die from stroke than Caucasians • Occur earlier in life • Reasons not fully understood, but have a higher rate of risk factors • ex: 41% have HTN

Uncontrollable Risk Factor • GENDER: WOMEN • 55, 000 more women than men experience stroke each year • Unique risk factors: • Oral Contraceptives • Pregnancy • Hormone replacement therapy • Post-menopausal with thick waist and high triglyceride levels • Suffer more migraines, increase risk 3 -6 times (National Stoke Association, 2009) Image from Microsoft Clipart

Uncontrollable Risk Factor • FAMILY HISTORY • Evidence suggests genes influence vulnerability to HTN & stroke • A region on: • Chromosome 13 in Caucasians • Chromosome 19 in African-Americans (Morrison, Brown, Kardia, Turner, & Boerwinkle, 2003) • Carotid intimalmedial wall thickness (IMT) • Surrogate measure of subclinical atherosclerosis • Strong predictor of future ischemic strokes • Homozygous for 6 A genotype • Genetically predisposed to produce less stromelysin 1 • High carotid artery wall thickness & greater risk of stroke Image from Microsoft Clipart (Humphries & Morgan, 2004)

Controllable Risk Factor & Inflammation • Inflammation can influence the development of atherosclerosis • Causes endothelial dysfunction • One of the earliest manifestations of atherosclerosis • Inflammatory markers associated: • Coronary disease development • Disease severity • Occurrence of coronary events • Progression of atherosclerosis may be associated with high concentrations of inflammatory markers (Humphries & Morgan, 2004)

TEST YOUR KNOWLEDGE • Select the controllable risk factors for stroke (Multiple answers) Hypertension GOOD JOB! SORRY! Cannot control if you Previous Stroke have a history of stroke OPPS! Age Cannot control age Hyperlipidemia GREAT!

TEST YOUR KNOWLEDGE • Men are at higher risk of stroke Sorry! Women are at higher risk of stroke & also have TRUE increased mortality. Yes! Women are at higher risk of stroke & also have FALSE increased mortality.

Types of Stroke • ISCHEMIC • Interruption of blood flow in a cerebral vessel • Most common type • Account for 70 -80% of strokes • HEMORRHAGIC • Bleeding into the brain tissue, from blood vessel rupture • Caused by: • HTN • Aneurysms • AVM • Head injury • Much higher fatality rate • 37 -38% of occurrence results in death (American Heart Association, 2010) (Porth, 2005) Image from Microsoft Clipart

Cell Ischemia • Reduced or absent blood flow deprives cell of needed nutrients • Effects occur quickly • No stored glucose in brain • Incapable of anaerobic metabolism (Porth, 2005)

Neuronal Injury: Excitotoxicity • Ischemia depletes neuronal energy stores causing energy dependent membrane ion pumps to fail • Results in increased extracellular glutamate concentration • Release of excitotoxic glutamate & aspartate open up calcium channels • Influx of calcium, sodium and chloride • Intracellular calcium responsible for activation of a series of destructive enzymes • Out flux of potassium • Resulting in irreversible neuronal damage • Results in release of cytokines and other mediators (Porth, 2005)

Inflammation Following Ischemia • Rapid production of inflammatory mediators • White blood cell (WBC) recruitment to ischemic area as early as 30 minutes • Capillary endothelium produces adhesive proteins causing WBCs to adhere to capillary lining • WBCs move into injured tissue • Phagocytize injured cells • Extent of inflammation can be determined by C-reactive protein levels (Porth, 2005) Image used with permission from http: //images. wellcome. ac. uk/

TEST YOUR KNOWLEDGE • Neural cell ischemia is caused from: Try again If the cell is not getting Too much energy available adequate blood flow, there to the cell is not enough energy available. Energy dependent GOOD JOB! No energy is getting to the membrane ion pumps fail cell. Try again Lack of phosphorus Phosphorus is not directly available related to this process Try again Decreased levels There are increased levels of glutamate.

Cerebellum • Stores learned sequences of movements • Fine tuning & coordination of movement produced elsewhere in brain • Integrates all information to produce fluid movements (Dubuc, 2002) Image used with permission from http: //thebrain. mcgill. ca/flash/i/i_06_cr/i_0 6_cr_mou/i_06_cr_mou. html#3

Movement • Motor cortex: • Sends signals to cerebellum • Communicates movement to make • Cerebellum: • Makes continuous adjustments • Final result: Hover the highlighted words for definition Cerebellum • Smooth movement, key with delicate maneuvers (Porth, 2005) Image used with permission from http: //thebrain. mcgill. ca/flash/i/i_06_ cr/i_06_cr_mou. html

Cerebellum Involvement • Receives proprioceptor input from vestibular system • Feedback from muscles, tendons, & joints • Indirect signals from somesthetic, visual, & auditory systems to provide background info for ongoing movement (Porth, 2005) (Mc. Gill University, 2002) • Can continuously assess status of each body part • Position • Rate of movement • Forces, such as gravity, opposing it

Dampening Muscle Movement • All body movements are pendular • Intact cerebellum analyzes proprioceptive information to predict: • Future position of moving parts • Speed of movement • Projected time course of movement • As movement approaches target, Cerebellum will: • Inhibit agonist muscles • Excite antagonist muscles (Porth, 2005) Image from Microsoft Clipart

Type of Movement “Require a burst of energy from an agonist muscle group; the movement is programmed from the start, so the movement proceeds from start to finish without modification” Simple Movement Click for Explanation Porth (2005, p. 1194) Image from Microsoft Clipart Self-terminating Movement: require smooth muscle sequence of coordinated agonist & antagonist movements programmed by higher Complex Movement brain centers to start, then are modified as the movement proceeds Click for Explanation

TEST YOUR KNOWLEDGE • Proprioreceptor input is: Meaningfulness of integrated Try again; sensory information from This is part of the various sensory systems somesthetic system. Any sensory nerve ending responding to stimuli from GOOD JOB! within body related to movement & spatial position The inner ear structures that OPPS! are associated with balance Vestibular apparatus, try and position sense again. Concerning perceptions of Try again; ‘where’ the stimulus is in This is part of the space and in relation to somesthetic system. body parts

TEST YOUR KNOWLEDGE • As movement approaches a target, the cerebellum will: Yes! Inhibit agonist muscles & Excite antagonist muscles Movement is pendulous, so muscles have to be stopped. Opps! Excite agonist muscles & Inhibit antagonist muscles Think this through again. Movement is pendulous.

Ataxia • People with ataxia experience • Failure of muscle control in arms and legs • Results in: • Lack of balance & coordination • Disturbance in gait (National Institute Of Neurological Disorders And Stroke, 2010) Image from Microsoft Clipart

Acquired (non-genetic) Ataxia • Conditions that can cause acquired ataxia • Stroke • Multiple Sclerosis • Tumors • Alcoholism • Peripheral neuropathy • Metabolic disorders • Vitamin deficiencies (National Institute Of Neurological Disorders And Stroke, 2010) Image from Microsoft Clipart

Ataxia after Stroke • Right side of cerebellum controls coordination on right side of body, left side controls left • When nerve cells are lost or damaged: • Provide less control to muscles • Resulting in: loss of coordination • During a stroke: • Blood supply is interrupted or severely reduced • Deprivation of oxygen and nutrients to brain tissue • Brain cells begin to die (Mayo Clinic Staff, 2009) Image from Microsoft Clipart

Recent Findings • 15% of all cerebral strokes involve the cerebellum (Timmann et al. , 2009) • Anterior lobe of cerebellum is involved in motor control • Concluded from a study containing 34 patients with cerebellar infarcts (Schmahmann, Macmore, & Vangel, 2009) Image from Microsoft Clipart

Cerebellar Ataxia • Decomposition of movement • Each component of the movement occurs separately instead of being blended into a smooth action (Porth, 2005) How does alcohol relate? Select the beer for the answer! “Ethanol specifically affects cerebellar function, persons who are inebriated often walk with a staggering and unsteady gait” Porth (2005, p. 1213) (Porth, 2005) Image from Microsoft Clipart

Ataxia • Rapid alternating movements are performed slowly and jerky • Such as pronation-supinationpronation of hands • Touching a target: • Movements broken down into small steps • Each movement goes too far, then overcompensated • DYSMETRIA (Porth, 2005) Image from Microsoft Clipart SELECT THE TARGET TO SEE AN ANIMATION OF DYSMETRIA

Clinical Pearl • Read the CT or MRI reports to identify where the infarct is located in the brain. If the cerebellum is involved, chances are ATAXIA will be exhibited in the patient Image from Microsoft Clipart

TEST YOUR KNOWLEDGE • Ataxia is: Weakness Try again Lack of coordination GOOD JOB! Impaired speech OPPS! No need to pay taxes Try again

TEST YOUR KNOWLEDGE • What part of the brain was infarcted if the patient has ataxia? AWESOME! Cerebellum Think again, motor cortex is involved in Motor Cortex movement, but not directly related to ataxia. Try again; Parietal Lobe not related to movement Almost there… Cerebrum look closer at the options.

TEST YOUR KNOWLEDGE • Ataxia in stroke is acquired ataxia. Yes! True Acquired ataxia is non-genetic. Opps! Ataxia after a stroke is not a genetic cause of ataxia. False Genetic ataxia is caused from mutations in genes.

National Institute of Health Stroke Scale (NIHSS) • Stroke scale functions: • Document and communicate • Baseline deficits • Changes over time • First used in 1989 • Administered in mean time of 6. 6 minutes • Interrater and intrarater agreement is good (Jensen & Lyden, 2006) Image from Microsoft Clipart

National Institute of Health Stroke Scale (NIHSS) • Strongly predicts the likelihood of recovery after stroke • Total score • > 16 high probability of death or severe disability • <6 predicts a good recovery (Duncan et al. , 2005) Image from Microsoft Clipart

National Institute of Health Stroke Scale (NIHSS) • 15 Item Clinical Deficit Scale • Assess: (Jensen & Lyden, 2006) • • • Image from Microsoft Clipart Level of Consciousness Gaze Vision Facial Palsy Arm & Leg Strength Limb Ataxia Neglect Dysarthria Aphasia REMEMBER: MUST BE ASSESSED IN ORDER LISTED

NIHSS Limb Ataxia “A few items consistently show poor agreement, notably ataxia, dysarthria, and facial weakness” Jensen & Lyden (2006, p. 2) YOU’RE NOT THE ONLY ONE WHO MAY MAKE AN ERROR SCORING ATAXIA!!!

NIHSS Limb Ataxia • Assesses evidence of a unilateral cerebellar lesion • Assesses incoordination from weakness • Test with eyes open, in intact visual field • Test on bilateral extremities (NIH Stroke Scale International, 2001) (National Institute Of Neurological Disorders And Stroke, 2001)

Evaluating Limb Ataxia • Scored if present out of proportion to weakness • Two instances when ataxia would not be assessed • Absent in patients who do not understand or are paralyzed • Untestable (UN) if amputation or joint fusion present (NIH Stroke Scale International, 2001) (National Institute Of Neurological Disorders And Stroke, 2001)

Finger-Nose-Finger Test • Ask patient to touch your index finger with his index finger and then back to his nose • Repeat enough times to fully assess for ataxia, moving your index finger each time to make a new target • Then repeat using other extremity (NIH Stroke Scale International, 2001) Image from Microsoft Clipart Click on picture of face to view example of fingernose-finger test with ataxia present

Heel-Shin Test • Ask patient to move right heel up and down the left shin • Repeat enough times fully assess for ataxia • Then repeat using other extremity (NIH Stroke Scale International, 2001) Image from Microsoft Clipart Click on picture to view example of heel-shin test with ataxia present

Limb Ataxia • SCALE DEFINITION • 0 • 1 • 2 • UN Absent (Not present or paralyzed) Present in 1 limb (an arm or a leg) Present in 2 limbs (both arms, both legs, or arm and leg on same side of body) Amputation or joint fusion (explain) • The link below will take you to the National Institute of Health Stroke Scale Training Video • Assessment #7 Limb Ataxia http: //www. youtube. com/watch? v=8 AXtl 3 QPH 7 Y&feature=related (NIH Stroke Scale International, 2001) Video used with permission from NIHSS English Training Campus

TEST YOUR KNOWLEDGE • Ataxia occurs because of muscle weakness after a stroke. False: True Ataxia is incoordination, not weakness! Great job! False Ataxia is incoordination, not weakness!

TEST YOUR KNOWLEDGE • Ataxia needs to be assessed prior to weakness in the NIH Stroke Scale. Think about the order of the exam. True Ataxia is assessed after weakness! Great job! False Ataxia is assessed after weakness!

TEST YOUR KNOWLEDGE • If the patient has weakness in the right arm and is unable to lift the arm off the bed, would ataxia be present? No, ataxia is not present because the patient is unable to perform the test. Yes The score would be absent or 0 due to paralysis. Great job! Ataxia is not present because the patient is No unable to perform the test. The score would be absent due to paralysis.

TEST YOUR KNOWLEDGE • The patient exhibits some weakness in the right arm and is able to perform the finger-nose-finger test. The patient misses the assessors finger. The patient completes test on left arm without difficulty. What score would be given for the upper extremity test? Try again! 0 Ataxia is present in R arm. GREAT JOB! 1 Try again! Ataxia is only present in the 2 R arm. Try again! Only score UN if amputation UN or joint fusion present.

Treatment • There is no current cure of ataxia following a cerebellar stroke • Physical & Occupational Therapy • Strengthen muscles • Assistive devices • Assist in walking and other activities of daily living (ADLs) (National Institute Of Neurological Disorders And Stroke, 2010) Image from Microsoft Clipart

Nurse Sensitive Outcomes • Impaired Mobility • Mobilize early to prevent complications • Active & Passive range of motion (ROM) • Participate in self-care & activities frequently • Teach safe use of assistive devices • Educate & Facilitate adaptation of home/work environment for maximal independence • Teach safety precautions • Expected outcomes: • Optimal independence with ADLs & mobility • Maintain safety precautions (Bader & Littlejohns, 2004)

Nurse Sensitive Outcomes Self-Care Deficit • • Evaluate ability to perform ADLs Consult occupational therapy (OT) Assess for risk of falls Expected outcomes: • Functional abilities recognized & advanced (Bader & Littlejohns, 2004)

Nurse Sensitive Outcomes Safety • Identify Fall Risk • Implement fall prevention strategies • Universal Fall Risk Interventions • Fall Precautions due to activity impairment • Expected outcome: • Effective in decreasing vulnerability to falls and related injury (Summers et al. , 2009)

Nurse Sensitive Outcomes Anticipatory grieving related to loss of functional abilities • Facilitate discussions to allow patient/family to voice concerns • Neuropsychiatry consult to evaluate cognitive vs. depressive issues • Rehabilitation consult to evaluate needs • Support Groups • Expected outcomes: • Supported & given resources to assist with coping (Bader & Littlejohns, 2004)

Coping • Challenges: • Loss of independence • May feel alone • Lead to depression & anxiety • Therapy or counseling may lessen sense of isolation and help cope • Can lead to increased stress on the patient • Habitual Stress • The physiologic & behavioral changes induced by generalized stress response can threaten homeostasis (Porth, 2005) (Mayo Clinic Staff, 2009)

Generalized Stress Response • Stroke is a life changing event people do not have time to prepare for • Stress can impact controllable risk factors for stroke • • • Hypertension High cholesterol Tobacco use Alcohol use Physical Inactivity Obesity

Generalized Stress Response (GSR) • Sympathetic Nervous System (SNS) • “Fight or Flight Response” • • Increased heart rate and strength of contraction Increased metabolic rate, stored fat released into circulation Bronchodilation in lungs Vasoconstriction of: • Skin • Gut § Decreased motility § Less insulin secreted • Kidneys • Pupils Dilate (Porth, 2005)

Renin-Angiotensin-Aldosterone Pathway Decreased blood flow to kidneys as response to SNS stimulation Aldosterone released from adrenal cortex turns on Na/K ATPase in kidneys (Porth, 2005) Renin released Activates angiotensinogen Converted into Angiotensin II Forms Angiotensin I a strong vasoconstrictor leads to increased blood volume and increased blood pressure, should increased blood flow to the kidneys

Hormone Involvement in GSR • Corticotropin-releasing Factor (CRF) • Released by the hypothalamus • Stimulates ACTH release • Adrenocorticotropic hormone (ACTH) • Released from the anterior pituitary gland • Stimulates synthesis and release of cortisol • Cortisol • Released from adrenal cortex • Affects many systems and processing in the body (Porth, 2005)

Effects of Cortisol • • • Cardiovascular • arterioles more responsive to sns • increased contractility • Renal • calcium lost in urine • Na+/K+ pump reabsorbs Na+ and H 2 O into blood, secretes K+ into urine Liver • stored glucose released into blood • Muscular Pancreas • decreased insulin release • Immune • Adipose tissue • lipids released from periphery, redeposited in trunk • Skeletal • decreased bone deposition (Porth, 2005) • actin and myosin break down • production of prostaglandins blocked • thymus atrophies • neutrophils can't leave blood • monocytes and macrophages less active

TEST YOUR KNOWLEDGE • Identify the most appropriate nursing diagnosis in terms of special needs when ataxia is present. Try again; Ataxia does not affect Impaired gas exchange breathing in the stroke patient. Try again; Ataxia does not affect Ineffective breathing pattern breathing in the stroke patient. Great job! Impaired physical mobility Very important to also consider fall risk! Try again! Ataxia affects movement, Impaired tissue perfusion not tissue perfusion.

TEST YOUR KNOWLEDGE • Treatment for ataxia in the stroke patient is: Try again; Used for stroke treatment, TPA but not for treating ataxia. Try again; Heparin Not used for treating ataxia. Try again; Movements are impaired Muscle Relaxers because of communication error in the brain. GREAT! Currently no treatment No Treatment Available available. PT & OT to help with function.

Case Study • A 67 year old male with a history of afib and prior stroke (with no deficits) was admitted from home with acute onset of nausea, generalized weakness, ataxia, and left sided weakness. Initial MRI noted a large acute ischemic infarct within the left cerebellum and smaller infarcted areas within the cerebellar vermis and right cerebellum with occlusion of the right internal carotid artery.

Case Study • What is the anticipated medical diagnosis of the patient? Try again; Stroke Be more specific Cerebellar Stroke GREAT!!! Try again; Weakness Be more specific.

Case Study • When tested for ataxia, it was present on the bilateral upper extremities. What score would be given according to the NIHSS? Opps! Ataxia is present, therefore, 0 0 cannot be the score. Try again; Ataxia is present in both 1 upper extremities. GREAT! Score 2 if present in bilateral upper or lower extremities, 2 or an arm and leg on the same side of the body.

Case Study • What appropriate nursing diagnosis would be given to this patient related to the presences of ataxia? Sorry, This would be appropriate, but Impair tissue perfusion not specific to the symptom of ataxia. Great! Think safety with patients experiencing ataxia! This patient has left sided Risk for injury: falls weakness, plus BUE ataxia. This could make using mobility devices harder. Try again, This could be present in the Impaired memory patient, but does not relate to ataxia.

The End • With the completion of the tutorial, you are now able to: • Describe pathophysiology of cerebellum as it relates to smooth muscle movements • Describe how ischemia to cerebellum causes ataxia in stroke patient • Identify presence of ataxia in stroke patient • Identify appropriate nursing interventions and outcomes

References American Association Of Neuroscience Nurses. (2008). Guide to the care of the hospitalized patient with ischemic stroke. 2 nd ed. Retrieved February 10, 2010, from http: //www. guideline. gov/ American Heart Association. (2010). Heart disease and stroke statistics - 2010 update. Retrieved from http: //www. americanheart. org Bader, M. , & Littlejohns, L. R. (2004). AANN core curriculum for neuroscience nursing (4 th ed. ). St. Louis, MO: Saunders. Duncan, P. W. , Zorowitz, R. , Bates, B. , Choi, J. Y. , Glasberg, J. J. , Graham, G. D. , . . . Reker, D. (2005). Management of adult stroke rehabilitation care: a clinical practice guideline. Stroke, 36, e 100 -e 143. doi: 10. 1161/01. STR. 0000180861. 54180. FF Humphries, S. , & Morgan, L. (2004). Genetic risk factors for stroke and carotid atherosclerosis: insights into pathophysiology from candidate gene approaches. The Lancet Neurology, April (3) 227 -236. Jensen, M. B. , & Lyden, P. (2006). Stroke scales: an update. Stroke Clinical Updates, XVI(1), 1 -7. Retrieved from http: //www. stroke. org/site/Doc. Server/SCU_-_Jan-Feb_2006. pdf? doc. ID=5166 Mayo Clinic Staff. (2009). Ataxia. Retrieved from http: //www. mayocli. Mayo Clinic Staff (2009) nic. com/health/ataxia/DS 00910/DSECTION%3 Dcauses Mc. Gill University. (2002). The brain from top to bottom. Retrieved March 12, 2010, from http: //thebrain. mcgill. ca/flash/index_d. html Morrison, A. C. , Brown, A. , Kardia, S. L. , Turner, S. T. , & Boerwinkle, E. (2003). Evaluating the context-dependent effect of family history of stroke in a genome scan for hypertension. Stroke, 34, 1170 -1175. doi: 10. 1161/01. STR. 0000068780. 47411. 16 Mosby (2002). Mosby's pocket dictionary of medicine, nursing, & allied health (4 th ed. ). St. Louis, MO: Mosby, Inc. National Institute Of Neurological Disorders And Stroke. (2010). NINDS ataxias and cerebellar or spinocerebellar degeneration information page. Retrieved from http: //www. ninds. nih. gov/disorders/ataxia. htm National Institute Of Neurological Disorders And Stroke. (2001). NIH stroke scale. Retrieved from http: //stroke. nih. gov National Stoke Association. (2009). Stroke risk factors am I at risk for a stroke? Retrieved from http: //www. stroke. org/site/Page. Server? pagename=RISK NIH Stroke Scale International. (2001). NIH stroke scale (NIHSS) in English. Retrieved from http: //www. nihstrokescale. org/ NIHSS English Training Campus. (21). 2 9 7 limb ataxia. Retrieved April 1, 2010, from http: //www. youtube. com/watch? v=8 AXtl 3 QPH 7 Y&feature=related Porth, C. M. (2005). Pathophysiology: concepts of altered health states (7 th ed. ) Lippincott. Schmahmann, J. D. , Macmore, J. , & Vangel, M. (2009). Cerebellar stroke without motor deficit: clinical evidence for motor and non- motor domains within the human cerebellum. Neuroscience, 162, 852 -861. Shah, S. (n. d. ). Pathophysiology of stroke. Retrieved March 12, 2010, from http: //www. ferne. org/ Summers, D. , Leonard, A. , Wentworth, D. , Saver, J. L. , Simpson, J. , Spilker, J. A. , . . . Mitchell, P. H. (2009). Comprehensive overview of nursing and interdisciplinary care of the acute ischemic stroke patient. A scientific statement from the American Heart Association. Stroke, 40. doi: 10. 1161/STROKEAHA. 109. 192362 Timmann, D. , Konczak, J. , Ilg, W. , Donchin, O. , Hermsdorfer, J. , Gizewski, E. R. , Schoch, B. (2009). Review: current advances in lesionsymptom mapping of the human cerebellum. Neuroscience, 162, 836 -851. Wellcome Images. (n. d. ). Wellcome Images. Retrieved February 12, 2010, from http: //images. wellcome. ac. uk/