Neuropathic pain in Guillain-Barre-Syndrome

We use the case of a mildly affected GBS patient with severe neuropathic pain to discuss the latter’s pathophysiology in general and the treatment for neuropathic pain in particular.
There is an excellent review article in BMJ 2014 which hints at the various drugs on the horizon, including some known substances whose application in neuropathic pain seems feasible (see below).

Neuropathic pain

  • Prophylaxis: in order to reduce the occurrence of neuropathic pain there is a good rationale for prophylactic treatment in certain cases, such as amputation, Zoster and nerve surgery, although not much good data has been published.
  • Classify: distinguish NP with autonomic features from that without, central versus peripheral (the latter often with autonomous signs)
  • Diagnosis: recognize the core features of pain character with good PPV (radiation, allodynia, hyperalgesia, autonomous sign if present, distribution along affected nerve structures)
  • Basic treatment
    • Stick to the basics: Despite the fact, that we Neurologists tend to think that NP is so special, we forget that basic nonsteroidal analgesics do work in NP; there is even a good pathophysiologic reason for that, since local cytokine production is influenced by at least the antiinflammatory substances (not acetaminophen, though).
    • Opiates: next is opiates, most often as a bridge to other approaches – still highly effective and reasonably well tolerated
    • alpha 2 delta blockers (gabapentinoids) work on the dorsal root ganglion and have been shown to be effective in many prototypical diseases
    • Na blockers (carbamazepine, phenytoin, lidocaine, lamotrigine)
    • NASRIs including tri- and tetracyclics and mirtazapin, as well as venlafaxine and duloxetine
  • Local treatment: only if the pathophysiological proces is focal – capsaicin and lidocain patch
  • Advanced treatment: for more advanced NP, ketamine seems to be the agent of choice as an NMDA blocker with all the problems arising. Further ideas could be: Baclofen, Clonidin. Many anticonvulsants (apart from those above) have been tested, not many survived, except in some diseases (trigeminal neuralgia for instance -> topiramate)
  • Experimental or future therapies: Allopurinol (ADP antagonist), Aprepipant (NK1 blocker), Memantine, Amantadine (both mild NMDA blockers), Cannabinoids (good preclinical data, moderate effect), cytokine inhibitors, NGF blockers

Pain in Guillain-Barré-Syndrome

I hesitate to repeat all the information to be found in the literature. Still it has to be said that pain is very prevalent, often preceding and also often following GBS, can take several forms (backache, interscapular, distal, skin, myalgia, …) and is often severe enough to run through the above list. Here is a good review article in Neurologia on this from 2015. The best case series has been published in Neuroloy in 2010.

On Spencer’s curve

2000px-znak_a-1-svg1In our recent ultrasound refresher course, I tried to give a talk on the vagaries of stenosis graduation (mainly) for extracranial stenoses. The gist of the talk is outlined in the following notes.

The Bernoulli principle

While Bernoulli’s equation is rather intricate, the underlying principle of conservation of flow along a stenosed tube is simple. Consider a tube with a short stenosis with laminar flow of a Newton fluid. Then the bigger area A1 multiplied with the flow  velocity v1 (take psv for simplicity, although this is not really correct) should be the same as the smaller area A2 multiplied with v2. Thus the increase of flow is proportional of A1 / A2, so that the reduction to a third of the area leads to an increase by the factor 3 of the flow velocity, a reduction to a tenth leads to ten times the flow velocity in the stenosis.img_7579

Adding friction

Since we usually don’t observe velocities higher than 5 m/sec, there must be a limiting principle and this is the resistance offered by the stenosis, which reduces flow in the whole vessel. This resistance can be approximated by the law of Hagen-Poiseuille and is proportional to the length of the stenosis, the inverse of r^4 and the inverse of viscosity. Again, this only holds for laminar flow and the case of blood offers some more complications, but the core message is: the longer the stenosis the higher the flow reduction. Also the flow reduction grows much more with decreasing vessel diameter than the flow velocity increase by Bernoulli’s principle can compensate. Very tight and long stenoses show a flow velocity reduction despite there high grade. If you  find a psv of only 2,4m/sec this might therefore mean either a mere medium grade stenosis or a very tight stenosis (near occlusion).img_7578

Spencer’s curve

Taking these two principles into account, Spencer and Reid (in their brilliant 1979 stroke article) deduced the famous curve now known as Spencer’s curve (see Alexandrov’s papers for a more detailled exposition).

Since at the time duplex sonography was technically not feasible, the Spencer curve is based on the theoretical assumption of a 2 mm stenosis and thus does not correct for the length of the stenosis (as well as the other factors mentioned below). This explains why the cw-doppler-data in their paper does not really fit the theoretical model. Still it is the best approximation we have to a theoretical foundation of stenosis quantification.

Measuring diameters

Diameter instead of area

Most of the studies have been done with angiographic imaging of stenoses or ultrasound measurements of the stenosis diameter rather than the area. Of course, the area could easily be calculated from the diameter (r^2 pi) if it were a circle, but then it isn’t. In ultrasound we could measure the area itself (if no shadowing artifacts are present), yet no one does really. Therefore you should remember that most of calculations of the stenosis area from the diameter are systematically invalid.

Where, when and how to measure diameters

For some absurd reason, Europeans kept to the local stenosis degree (i.e., diameter of perfused lumen divided by the original vessel diameter), at least in their ECST trial, while the NASCET trial used the more reasonable distal stenosis degree (i.e., minimal lumen diameter divided by non-stenosed distal ICA diameter). Since the ICA bulb varies in its bulbiness and distends with age and blood pressure (and with stenosis degree), the local stenosis degree is usually a shot in the dark. The distal (NASCET) degree suffers from pseudoocclusion, i.e., collapse of the distal vessel in very high grade stenosis. All attempts to calculate the NASCET stenosis degree from ECST and vice versa are irrational.

Being faithful to both traditions, I measure all the lumina (minimal lumen, original vessel lumen, distal lumen). The only really interesting number is the residual diameter (combined with the length of the minimal lumen), because this determines the hemodynamic compromise.

Other important factors


Neither is blood a Newton fluid, nor is all the viscosity (rarely measured today) explained by the hematocrit alone. Yet the hematocrit is an important number to factor into your interpretation of ultrasound data. You should note it.


Every vessel wall abnormality leads to small perturbations of flow and thus turbulence. Turbulence reduces anterograde flow and thus reduces the distal pressure after a stenosis. While very hard to quantify it is essential to mention turbulent flow when you see it. Remember that to distinguish retrograde (i.e. turbulent) flow from flow increase with aliasing you need to look at the color bar on the side of your duplex image, noting that flow increase jumps over the upper limit of the color spectrum while retrograd flow (usually) passes the black zero flow region.


decreases over the lifetime, even more if severe hypertension or calcification of vessel walls is present. This, again, is very hard to quantify, but often easy to recognize qualitatively in your duplex image, when you recognize the pulsation of the vessel wall. Reduced elasticity has to lead to increased flow velocities.


Since blood flow is not continuous but pulsatile and this in varying shapes, we should really be using mean flows in our stenosis calculations. This has historically not been done. As a consequence, valve abnormalities (aortic stenosis, insufficiency) have to be factored in, when we try to calculate the stenosis degree from peak systolic velocities.

Blood pressure and atrial fibrillation

The (pulsating) blood pressure is the driving force of cerebral blood flow, trying to overcome venous and intracerebral pressure as well as the distal blood pressure offered by collaterals (see below). At least, you should note the blood pressure and relativize your stenosis graduation in cases of extreme values. When the patient has atrial fibrillation, you probably should use an “average” heartbeat rather than the extreme values. But bear in mind that absolute arrhythmia is a risk factor for arterioarterial embolization in itself.

The geometry of the stenosis

usually is far from being that of a tube. Rather, the blood flow curves around plaques, rotating and hitting small plaques on the distal wall. Again, the effects are impossible to quantify, but at least the geometry should be noted. The shape of the stenosis area should be remarked upon, if it isn’t circular.

The role of collaterals

The pressure difference along a stenosis is not only determined by the resistance of the stenosis itself, but also by the collateral blood flow which leads to an increase of distal pressure (mostly but not only in diastole). This leads to a reduction of the blood flow velocity in the case of good collateralization, thus also reduced flow velocities.

The danger of a stenosis

In the neurovascular clinic, I try to estimate four risks of a stenosis: the hemodynamic risk (what happens if the stenosis were to increase?), the embolic risk (how high is the risk of an embolic event from the stenosis?), risk factors and other risks.

Hemodynamic risk

The hemodynamic risk is determined by

  • the current hemodynamic compromise (jet flow velocity, CCA flow vs. ICA flow, pulsatilities, MCA flow, CO2 reserve)
  • the dynamics of the stenosis (how long has this been going on? was there time to develop collaterals?)
  • the completeness of the circle of Willis (variations such as A1 hypoplasia, Pcomm hypoplasia)
  • secondary stenoses in the collateral circulation.

The problem is that we cannot foresee whether the stenosis will be slowly progressive or suddenly close up (as in plaque rupture). At least in asymptomatic stenoses I require CT- or MR-angiography to determine the completeness of the circle of Willis.

Embolic risk

The embolic risk is determined by

  • Plaque morphology and
  • Plaque type
  • Whether the atherosclerotic process is active or burnt out.
    As in coronaries, it is not reasonable to revascularise every severe asymptomatic stenosis. But in a patient where the overall atherosclerotic process is currently active (after an NSTEMI, say), we can expect the plaques to rupture.
  • Previous embolic events can be noted on MRI.
  • Emboli detection
  • Is the anti-platelet medication working? Multiplate or similar tests.

Risk factors

  • Did the patient stop smoking? How long ago?
  • Can we use high dose statins in this patient? Statins are highly effective against plaque deterioration, but also have serious side effects (less exercise tolerance, diabetes, muscle problems), especially in the high doses we like to use for severe stenosis.
  • Is the patient’s blood pressure controllable? Note that severe stenosis lead to very labile blood pressures as one of the most important sensors of the system is damped.
  • Exercise? Although this has not been studied properly in carotid artery stenosis, I surmise that health by fitness should improve the prognosis of carotid artery stenosis.

Other risks

  • Central or mixed sleep apnea syndrome – very prevalent among ICA stenosis patients, leading to a bag of systemic problems, not the least being poor blood pressure control.
  • Bad blood pressure control (see above)
  • Development of secondary stenoses in the collateral vessels (contralateral, ECA, …)
  • Development of a collateral rete with its danger of bleeding


I don’t see any better physical theories coming. Also, we can never expect better data than NASCET and this is a bad foundation. Therefore you have to tackle all the complexities outlined above and refrain from simplifying an ICA stenosis to a mere number (always the worst approach).




An algorithm for starting oral anticoagulants after stroke

Once you identified the heart as the emboligenic source of your stroke unit patient’s stroke, the question arises of why, when and how you institute anticoagulation. This hasn’t gotten any easier with all the new drug options, Big Pharma push and the resulting trust we are supposed have in DOACs.

In this short blog entry, I will list my 6-step program for starting oral anticoagulants after an ischemic event. Thanks to the great acronym creator, here is the mnemonic for it: SHuTOFF DOAC.

  • Stroke risk
  • Hemorrhage risk
  • Timing
  • Oral agents
  • Formulary
  • Follow-up

Stroke risk

Calculate the risk of recurrent stroke, if you find data.

  • Atrial fibrillation: 12% vs 1-3%/a under OAC, use a CHADSVASC-calculator for individualized data, bearing in mind that most of the underlying studies were in a primary prevention setting.
  • Atrial thrombus: An atrial thrombus is essentially just a sign of (possibly undetected) afib and insufficient anticoagulation, although it can occur in otherwise bad hearts (see this huge collection of TEE+ pts). Still, we would like to know how more acute the danger of recurrent stroke is, if you find an atrial thrombus on TEE. Or – as increasingly happens – on CTA, when you stumble on a left atrial appendage filling deficit by chance. Does it double or triple? Or stay the same? No proper data found on this. 
  • Ventricular thrombus: Apart from the fact that those are easier to find (TTE suffices) and that ventricular thrombi are due to bad hearts (large MI, severe cardiomyopathy) in general, no data can be found on the rate of acute stroke recurrence in this setting. In the long run (1/2a) it is very impressive (50%) according to very old studies, seemingly lowered by anticoagulation (to 30% in this analysis).
  • Mechanical heart valves: Few studies exist, since everyone thinks these patients absolutely have to be anticoagulated. Only part of the embolic risk is due to the valve itself, the rest comes from afib, especially with mitral valve replacement.
    This 1994 review finds a risk of 4 per 100 pt. years without anticoagulation, reduced to 2,2 by ASS and 1 by VKA. This newer analysis of pts. with St. Jude valves finds similar rates of embolism with OAC.
  • Bioprosthetic heart valves carry a significantly lower risk, about half the number of embolic events seems a good estimate.
  • Low EF: Although we left routine anticoagulation for low EF in primary prophylaxis after the WATCH and WARCEF studies (where a reduction in embolic strokes was offset by the increased bleeding risk for OAC as compared with ASS), a cardioembolic stroke in the setting of severely reduced EF and sinus rhythm should probably trigger oral anticoagulation. I could not find proper data for the stroke risk after an embolic event happened.
  • PFO plus/minus ASA: The risk is extremely low, if no proof of the paradoxical mechanism can be established (no pulmonary embolism, no DVT). Otherwise the risk should be roughly the same as the risk of recurrent venous thrombosis (determined by genetics, mobility, triggers and so on) times the cross-embolism-factor (how many of those embolisms cross over through the PFO, can be measured semiquantitatively in the bubble test, this is my personal invention :-)).

Hemorrhage risk

Risk for spontaneous ICH under OAC

Find and optimize risk factors for hemorrhagic complications under OAC, in particular ICH. For atrial fibrillation there is the simplified  HASBLED-score, but some particular risk factors might benefit from more intensive workup.

  • The A4F complex of the elderly
    • Age
    • Alzheimer’s
    • Apolipoprotein ε2, ε4
    • Amyloid angiopathy
    • Falls
  • Alcohol
  • Altered coagulation (cirrhosis and the like, low platelets)
  • Adherence problems
  • Diabetes
  • Hypertension
  • Interacting medication
    Obviously, the more drugs a patient takes, the higher the risk. With antiplatelet comedication, you double the risk with monotherapy and triple it with dual therapy (or even worse with the newer antiplatelets ticagrelor, cangrelor)
  • Liver and kidney problems
  • MRI markers: leukoaraiosis (no proper gold standard for quantification, may use Fazekas score or volume of white matter hyperintensities, no cutoff established) and number of microbleeds (no proper cutoff because the sensitivity depends on the MRI sequence used and field strength)

Risk for hemorrhagic transformation of the stroke

The acute setting of a stroke raises the obvious concern of bleeding into the stroke (either minor as hemorrhagic transformation or as parenchematous hematoma). Since the detection of hemorrhagic transformation is a matter of the sensitivity of your imaging technique (proportional to the field strength of your scanner, SWI outperforming T2*), only parenchematous hematoma (as can be seen with any old CT or even on ultrasound) should be used to judge the danger of anticoagulation and the reported rates vary between 10 and 30% of cardioembolic strokes. It is unclear, though, whether this rate increases with oral anticoagulation (it does with heparin and LMWH, but those are way more intense) and for how long the danger persists – see next step.


The 1-3-6-12 rule

There is practically no data on when to start OACs after stroke, so we use the guidelines (ESC 2016) with their practical 1-3-6-12d rule (TIA/NIHSS 0, NIHSS < 8, 8-15, > 15), although they don’t regulate the case of hemorrhagically transformed or parenchymatous hematoma in stroke.


And in the meantime?

  • It is unclear whether ASS makes sense for bridging until OAC in afib – it seems to not hurt much after cardioembolic stroke, though. The guidelines recommend ASS bridging.
  • Heparin or OAC bridging (at least with Warfarin) confers no benefit in the huge studies analyzed in Sandercock’s Cochrane analysis. Whether (lower dosed) DOACs could be used in this setting (analogous to, say, half-hearted LMWH treatment) is also an open question.

Bear in mind that the risk for recurrent stroke during the inpatient period is extremely low (around 3% in simple afib patients – old data, but replicated in modern case series such as this one). It is a daunting question when to bridge in the higher risk groups, such as mechanical heart valves. Most reviews recommend 7-14 days (without proper data to back that recommendation).

Oral anticoagulant

In the next step you have to choose among the 5 options. Consider the acronym DOAC:

  • Drugs: what other drugs is the patient on, what are the possible interactions?
  • Organs: is the patient at risk for renal insufficiency or liver failure?
  • Age: since the lightweight elderly are prone to renal failure even with borderline creatinine, age is a risk factor for all DOACs.
  • Compliance: DOACs aren’t very forgiving, if you forget some doses, VKA usually are.


Lookup the dose according to all of the above (most of the DOACs have a low and high dose regime, according to risk factors among the above)


Do you have to ensure lab checks? This is obvious and well established for VKAs. It should also be reasonable to check creatinines in patients at risk for renal failure. Rarely, if ever, are drug levels or anti-Xa-activity needed for standard therapy. When it comes to acute surgery, tPA or in case of bleeding, having drug levels at hand is, well, handy.