Reworking the Spine

Motivation: During medical school, when I told a notable surgeon that I intended to enter neurology, he smirked while trying to suction clotted blood and then said, "If you like banging your head against a wall, then go to neurology."  The implication being, of course, that neurologists have few cures.  While I disagree with the surgeon's assessment of neurology, even I was surprised by a remarkable article in Lancet this year that demonstrated for the first time recovery of ability to stand after complete spinal cord motor injury.  And, this experiment did not even use stem cells.

The theory driving this experiment is rooted in the observation that mammalian spinal cords can generate locomotor output even in absence of central input.  The hypothesis is that if these spinal circuits can be stimulated, then people with spinal cord injury may be able to stand once more.

Paper: Harkema, S., Gerasimenko, Y., Hodes, J., et. al. "Effect of epidural stimulation of the lumbosacral spinal cord on voluntary movement, standing, and assisted stepping after motor complete paraplegia: a case study." Lancet (2011); 377: 1938-47.

Method: This case study examined a single subject: a 23 year old man who was paraplegic from C7-T1 subluxation after a motor vehicle accident in 2006.  He had no contraction of trunk or leg muscles and only weak movements of hand muscles.  He retained, however, light-touch and pinprick sensation in lower extremities.  From 2007 to 2009, patient received 108 hours of step training and 54 hours of stand training during rehab with no clinical improvement.  An epidural spinal cord stimulation unit was then placed on the patient to stimulate the lumbosacral epidural region at location T11-L1 (to control spinal cord segments L1-S1).

Results:
Standing: Epidural stimulation (15 Hz, 8V) of the L5-S1 segment along with extension of legs resulted in the patient being able to stand in sustained posture with full weight bearing for more than four minutes.  Interestingly, the sustained standing posture was triggered by loading weight onto the legs.  Simultaneous EMG showed coordinated contraction of both flexors and extensors.  Of note, during standing, spontaneous postural changes occurred in response to shifts in center of gravity sagitally.

Walking: Epidural stimulation at 30-40 Hz and sensory cues (such as manually positioned stepping posture) generated walking-like motor patterns.  Without stimulation, manual positioning elicited no motor response.

Function Recovery: After 80 training sessions with epidural simulation over seven months, patient recovered voluntary movement of toe extension and ankle and leg stimulation while receiving spinal stimulation.  During epidural stimulation, patient also recovered bladder function with minimal post void residuals.  He also recovered function of other autonomic nervous system processes and gained weight by 18%.

Discussion: This paper is not only a potential paradigm changing case report in the field of spinal cord injury but also illustrates concepts that affect our understanding of the nervous system.  First, traditionally in our mind's eye, we view the sensory system and motor system as fairly indpendent pieces - one traveling up the dorsal part of the spinal cord and the other descending down the ventral part.  This paper shows that for basic tasks like standing, integration of sensory input and motor output occurs at multiple levels beginning with the spinal cord. So, while evaluating patients with gait difficulty, sensory deficits must be considered along with weakness.  Secondly, this paper extends the trend in our understanding that complex motions like walking occur as a result of interactions between multiple centers in the nervous system.  Clearly, part of the coordination process occur in the spinal cord itself.  Encouragingly, this distributive process may help us recover from seemingly "irremediable" defects such as complete motor spinal cord injury with the help of prosthetic electrical devices.

While encouraging, this paper obviously has many limitations.  Before epidural stimulation becomes the next glamorous procedure, this finding has to be replicated in more than the one case report.  Also, the patient in this case report is a healthy man in his 20s who had an accident.  It is unclear how this result generalizes to older nervous systems of patients in their 70s.  Nonetheless, for the final post of the year, this paper shows how seemingly impossible medical advances keep happening.

Aortic Stenosis - How Bad?

Motivation: If you listen closely enough, you will hear a murmur.  That has been my feeling about listening to murmurs over the aortic valve.  Almost everyone has a "soft ejection murmur."  The question, of course, is how tight is the aortic valve.  We have all heard cautionary tales about the lack of correlation of murmur intensity with aortic valve area.  During morning rounds, an attending suggested using the physical exam sign of "brachioradial delay" as a measure of severity of aortic stenosis.  How good is the sign?

For background, brachioradial delay is assessed by gently palpating the brachial and radial pulses simultaneously.  If there is a palpable delay between the brachial and radial pulses, then "brachioradial delay" is present.  From a pathophysiology viewpoint, the quicker the upstroke of the arterial pulse the quicker the pulse pressure wavefront spreads through the arterial tree.  In aortic stenosis, the upstroke of the arterial pulse is slower allowing some of the energy to be absorbed by circumferential stretch of the arteries.  Consequently, with a slow upstroke, there is a palpable delay in the spread of the pulse upstroke between proximal and distal arteries.

Paper: Leach, R.M. and McBrien, D.J. "Brachioradial delay: a new clinical indicator of the severity of aortic stenosis." Lancet (1990); 335: 1199-201.

Methods: Patients presenting at echocardiography clinic at Worthington Hospital (U.K.) were prospectively assessed by four clinicians about the presence of brachioradial delay.  Subjects were not preselected by any diagnosis.  The sign was counted positive if all four clinicians agreed.  Subsequently, for all the patients, the delay between the brachial and radial pulses was timed, and echocardiography was done in all patients.  In the paper, severe aortic stenosis was defined as aortic valve area of 0.5-0.75 sqcm.

Results:
Patient selection: Among the patients assessed, there were 33 patients with aortic stenosis and 25 patients with other heart diseases (9 heart failure, 4 MR, 3 post MI, 3 HOCM, 2 aortic regurg, 2 afib, 1 bicuspid aortic valve, 1 heart transplant).  Of the 33 patients with aortic stenosis, 17 had severe aortic stenosis (valve area between 0.5-0.75 sqcm).  The authors also reported on 27 controls without heart disease who were age and sex matched.

Control Subjects: For none of the 27 control subjects was a brachioradial delay palpable.  On measurement by pressure transducers,  the mean brachioradial delay was 24.3 msec below age 55 and 21.7 msec for those over age 75.  None of these delays were palpable.

Aortic Stenosis: In the 17 patients with "severe" aortic stenosis (valve area 0.5-0.75 sqcm), the brachioradial delay was palpable in all patients.  For 16 patients with mild aortic stenosis (valve area > 0.75 sqcm), brachioradial delay was palpable in only 6 out of 16 patients.

Other Heart Conditions: In 25 patients with other heart conditions, brachioradial delay was palpable in one patient with hypertrophic obstructive cardiomyopathy.  In no other patient was brachioradial delay palpable.

Discussion: This paper is remarkable in many ways.  I was surprised to see a novel physical exam sign for aortic stenosis described in the relatively recent past (1990).  Also surprising is the 100% sensitivity of this sign for aortic stenosis with valve area <0.75 sqcm.  The physical exam sign is also good because to determine a positive sign, you do not need to have many years of experience examining normal subjects.   The sign is a relative palpable delay between brachial and radial arteries.  Of note, the sensitivity of the sign falls off rapidly as the valve area increases above 0.75 sqcm (only 6/16 positive).

The paper, however, also has many weaknesses.  First of all, there are relatively few subjects examined.  Secondly, the specificity of the sign is very poorly established.  The group with "other" heart diseases was heterogeneous with few representatives of each type of cardiac pathology.  Finally, of note, what is called "severe" aortic stenosis (valve area <0.75 sqcm) would likely be termed critical aortic stenosis now (at least in the U.S.) while the mild aortic stenosis in the paper would be severe aortic stenosis at present (valve area 0.75 to 1 sqcm).  Despite these weakness, I think that the brachioradial delay is a good test to assess for critical AS in a patient with classic AS murmur.

DVT Prophylaxis - Surprising Truths

Motivation: Frankly, DVT prophylaxis seems like a lot of voodoo to me.  Most patients who become hospitalized have probably been sick in bed at home for some days, and many continue to be bed-bound after discharge.  During the few days of hospitalization, I often wonder what difference is made by daily stabs in the stomach with heparin.  Yet, there is increasing institutional push to remember to use heparin prophylaxis.  I was browsing for some evidence for DVT prophylaxis when I came across American College of Physician systematic review about this very topic published this year.  The results are surprising.

Paper: Qaseem, A., Chou, R., Humphrey, L., et. al. "Venous Thromboembolism Prophylaxis in Hospitalized Patients: A Clinical Practice Guideline from the American College of Physicians."  Ann. Intern Med. (2011) 155: 625-632.

Methods: Systematic review of published randomized trials from 1950 to 2011.  Primary outcome was total mortality 120 days after randomization.  Secondary outcomes were symptomatic DVT, all PE, fatal PE, all bleeding, and major bleeding.  The review separated analysis for patients with and without acute stroke.

Results:
Effect of heparin prophylaxis versus no prophylaxis:
Medical patients without stroke - The review found ten trials (total of 20,717 patients) of patients without stroke.  There was NO significant effect on mortality at 120 days (RR: 0.94, CI: 0.84-1.04).  Heparin was associated with reduced risk for PE (RR: 0.69, CI: 0.52-0.90) but also increased risk of any bleeding (RR: 1.34, CI: 1.08-1.66). The differences in major bleeding and symptomatic DVT were not significant. In summary, heparin use prevents 4 PE per 1000 treated but causes 9 events of any bleeding per 1000 treated.
Acute Stroke - Review found 8 trials (total of 15,405 patients).  Pooled results showed NO significant reduction in mortality, PE, or symptomatic DVT. Prophylaxis was associated with increased risk for major bleeding (RR: 1.66, CI: 1.20-2.28). Pooled data was, however, pretty heterogenous in findings (wide spread in data).  The largest randomized trial with acute stroke had 14,578 patients and found NO reduction in mortality or PE.  However, a significant reduction in recurrent ischemic stroke was detected (RR: 0.65, CI: 0.54-0.80) at the risk of increased risk of hemorrhagic stroke or serious extracranial hemorrhage (RR: 1.73, CI: 1.22-2.46).

Low-Molecular Weight Heparin versus Unfractionated Heparin:
Medical patients without acute stroke: NO statistical difference in mortality, PE, or major bleeding events.
Acute Stroke: NO statistical difference in mortality, PE, or bleeding events.

Compression Stockings versus no stockings:
Sparse data (three trials, 2518 patients) making separation of general medical patients from patients with acute stroke difficult.  Overall, compression stockings did NOT reduce mortality, symptomatic DVT, or PE.  Risk for lower extremity skin damage was significantly increased among patients wearing stockings (RR: 4.02, CI: 2.34-6.91) conferring risk of 39 events per 1000 treated.

Discussion: To me, the most surpirsing part of the review was that despite the large pooled cohort size (>20,000 patients), there was no mortality benefit with heparin prophylaxis four months post-randomization.  The reduction in PE risk by about 30% presumably involves decreased risk of small PE.  As expected, the cost of reducing PE is increased bleeding events.  Amazingly, acute stroke patients did not have similar PE risk reduction despite a large cohort size.  Heparin use in acute stroke is a different balance between reduction in recurrent stroke (reduction by about 35%) compared to increased risk of major bleeds, including intracranial bleeds.  The review also helped clarify a couple of other misconceptions that I had.  Overall, low molecular weight heparin is no better than unfractionated heparin other than once a day dosing versus three times daily dosing.  I had thought that LMWH was better than unfractionated heparin.  Also, compression stockings proved to be pretty useless.  There is no demonstrable benefit while incurring increased risk of lower extremity skin damage.  On balance, there appears to be increased harm.  The review did not cover pneumatic compression devices.

One caveat to keep in mind in these large systematic reviews is that by pooling data, a lot of granular differences among subgroups are lost.  For example, ICU patients may have different risks and benefits.  There are also number of other cohorts such as patients with cirrhosis or kidney disease who may benefit variably with heparin.  When evaluating 30,000 patients, only effects that are consistent across entire groups are apparent.  One way in which this paper changes my perspective on DVT prophylaxis is that I will be less hesitant to hold prophylaxis in patients at risk for bleeding (after all, not saving lives with heparin).  And, I will stop pushing for stockings - good for Christmas but probably not for preventing PE.

Valves of the Right Stuff

Motivation: Morning rounds with a cardiologist is like going from room to room and trying to be a human echo machines.  Is there a valvular problem? The safe answer is almost always yes.  You may not be able to hear it, but the attending can.  Although human beings have refined their ears to distinguish harsh, blowing, and soft transvalvular flow sounds, the ability to fix valvular disease has lagged behind.  Artifical valves have major problems.  Mechanical valves require life long anti-coagulation, and dead tissue valves have finite lifespan.  A surgeon recently showed me the third way: growing valves out of your own tissue.  Sounds like fiction, but the patient did just fine after the tricuspid valve repair operation.  Here is a case series from Italy that demonstrates the magic.

Paper: Quarti, A. et. al. "Preliminary experience in the use of an extracellular matrix to repair congenital heart diseases." Interactive Cardiovascular and Thoracic Surgery (2011) article in press.

Methods: Between 2009 and 2011, 26 patients with congenital heart defect underwent surgery using an extracellular matrix patch (manufactured by CorMatrix).  The matrix was constructed from porcine small intestinal submucosa with expectation that native heart tissue would grow over the matrix.  The immediate post-operative course was reported.

Results:
Patients: Surgery was performed in 26 patients (mean age 6.4 years, range of 8 days to 32 years):

• 10 for pulmonary patch arterioplasty
• 9 for valve leaflet repair (including tricuspid, pulmonary, aortic, and mitral valves)
• 4 for ascending aortic patch aortoplasty
• 3 for aortic arch reconstruction
• 1 for right ventricular outflow tract obstruction

Results: There were no deaths in the peri-operative period.  At follow-up (mean 13.2 months, range 4-25 months), there was no evidence of thrombosis, disruption, shrinkage, leakage, or patch calcification on echo and CXR. 

For the patients with valve repair, follow-up echo only showed trivial to mild regurgitation.  No valve repair required reoperation.  Intial followup of the valve repair cohort (mean of 12.5 months) did not show evidence of progression of regurgitation. 

For cases in which extracellular matrix was used as vascular patch (18 cases), two had pulmonary artery stenosis distal to the patch.  One required operative repair.

Discussion: This paper may be part of the intial foundations of a marked change in valve repair surgery.  If the results eventually hold up in larger study, many of the long-term complications of valve repair surgery such as anti-coagulation, thrombogenic risk, and risk of endocarditis will be significantly decreased.  At present, however, this paper probably generates more questions than answers.  First of all, the follow-up is short, and questions about long-term viability of the ECM repair remain.  Also, most of the subjects were children, and older adults may repopulate the matrix at a different rate than children making extension of the results to adults problematic.  This paper probably lays the groundwork for larger randomized trials.  Finally, the paper does not mention the funding source.  In subsequent trials, it would be preferable if CorMatrix is not part of the trials.