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.

Drop attacks

splash-water-1362224788t1gMedical terminology knows 5 reasons for people to fall unaided: common fall, syncope, collapse, seizure and drop attack.

A drop attack consist of the loss of lower extremity tone, leading to collapse, but decidedly without disturbance of consciousness (as opposed to syncopes) and without accompanying neurological or other signs or symptoms, in particular without dizziness or faintness, diplopia etc. Peculiarly, the attacks occur while walking, not standing or sitting. They seem to be quite prevalent, constituting a significant percentage of falls in the elderly.

The concept of drop attacks is very old and yet, there is not much published about it. As far as I got in my literature review, a 1986 series in Neurology has the most modern data (an astonishing 108 patients!). Apart from that you have to work through case reports and chapters in neurology textbooks, such as Neurological Differential Diagnosis – a cased-based approach.

The prototypical patient is a woman over forty who reports falling forward while hurriedly walking on the pavement, as if someone had pushed her, without warning, the legs giving way. She might even have injured herself. Once down, she could get up again after a few seconds, without feeling dizzy, nauseus or unsteady.

The differential diagnosis is huge, since so many diseases have been associated with drop attacks, and in some cases falsely so.

Hemodynamic ischemia

Take vertebrobasilar ischemia, for instance. Before the advent of MRI and CTA, many anomalies in the posterior circulation were interpreted as evidence of pathology, such as hypoplastic posterior communicating arteries, asymmetry of one vertebral artery or hypoplastic V4 segments. In practice, it seems to be nearly impossible to get isolated drop attacks (without vertigo!) from a hemodynamic basilar compromise. In a series of 83 proven basilar artery occlusions from basilar stenoses, prodromi included “drop attacks” in only 4 cases and these were accompanied by vertigo in 3 (Ferbert, Stroke 1990). Similarly rare, yet pathophysiologically more reasonable, is the case of a high grade carotid artery stenosis with contralateral hypoplastic A1-segment – when the compromised ICA supplies both anterior cerebral arteries.

It is interesting to note that the stroke rate of people with drop attacks was not increased as compared to age-matched controls in the 1986 series.

Systemic hypoperfusion (aka syncope without dizziness)

The classical mechanisms of syncope (orthostatic, neurocardiogenic etc., aortic stenosis) practically always lead to disturbance of consciousness or at least dizziness. There is just one exception: rhythmogenic drop attacks (Adam-Stokes attacks). In the above mentioned case series this constituted a sizable percentage (13%). Although I would think that a careful reevaluation reduce that number considerably, I concede that an event recorder is a reasonable investment for recurring drop attacks, not the least, because the gadgets have become so simple to implant.

A special case is carotid hypersensitivity syndrome, where a vagal mechanism due to head rotation or local pressure is usually hypothesized. To be honest, I haven’t seen many cases of this, despite the fact that I am working in a neurovascular lab much of my spare time, so it can’t be that frequent.


Atonic (or astatic) seizures are well-known phenomena in pediatric neurology, arising in Lennox-Gastaut-syndrome, Doose syndrome and other epilepsies. It is rare as a manifestation of adult onset epilepsy, all the less in the elderly, yet the classical temporal lobe epilepsy can lead to temporal lobe syncopes or temporal lobe drop attacks in this age group as in any. 

In these modern times of weird autoimmune encephalitis variants, LGI1-antibody encephalitis has been reported to cause drop attacks even before it’s more typical facio-brachio-crural dystonic seizures.

Movement disorders

In (advanced) Parkinson’s you can be attacked by drops, usually with polypharmacy and fluctuating clinical course (on/off phenomena, freezing). Patients with Progressive Supranuclear Palsy tend to fall backward rather than forward, yet this can be described as a drop attack as well. Both diseases should present with clinical hints at the movement disorder.

Paroxysmal kinesiogenic dystonia has been proposed as an imitator of epilepsy and you could assume that this can lead to drop attacks as well, although I could not find a case report of this. At any rate of occurrence, a family history should help.

Negative myoclonus

This can be an expression of epilepsy (particularly, if focal as in benign partial epilepsy, see above) or a more generalized encephalopathy such as hepatic or toxic, leading to Asterixis (think of Pregabalin, Oxcarbazepine and toxic doses of any central acting drug). History, a hunt for the “flapping tremor” and lab works should rule this out.

Vestibular drop attacks

An acute and temporary disturbance in otolith function can lead to drop attacks. This has been eponymized by Tumarkin who coined the term otolith crisis in the thirties. The attacks are not the correlate of an acute Meniere’s endolymphatic hydrops, but due to unstable otolith function. In contrast to most other drop attacks there ought to be a sensation of vertigo, i.e., of movement of the outer world, yet only few patients can actually report this.

Theoretically, other vestibular disorders, in particular superior canal dehiscence syndrome, should be able to provoke vestibular drop attacks as well, yet there are no case reports.

(Cranio-)Cervical dysfunction

Quite a few diseases of the cervical myelon and the craniocervical junction can lead to temporary compression or dysfunction of either the pyramidal tract or the dorsal column afferent fibres, thus leading to either loss of tone or loss of feeling in the legs, hence the drop attack.

  • Posterior fossa tumors
  • Subacute combined degeneration (Vitamin B12)
  • Chiari Type I
  • Cervical spinal canal stenosis and other causes of cord compression

Other rare causes

  • Third ventricle tumors (colloid cyst, pineal cyst) – usually with postural headache
  • Isolated cataplexy as an abortive variant of narcolepsy
  • Coffin-Lowry-syndrome – stimulus-induced drop events

Climate change


The earth might be warming up and so might our patients in the ICU. It is easy to fall into the Fever ➝ CRP ➝ antibiotics trap, but our goal is to be more responsible.


  • Raised temperature: fever vs. hyperthermia
  • Central fever
  • Stroke and fever
  • Temperature management strategies for stroke
  • Infectious causes of fever
  • Noninfectious causes of fever
  • References

Raised temperature

might be fever or hyperthermia.

Fever is more common and defined by a raised hypothalamic setpoint, due to

  • infectious or
  • other inflammatory reasons, or due to
  • central stimulation

of the hypothalamus (“central fever”, e.g. blood in brain, see below). Note that CRP does not really distinguish between the three causes of fever, while procalcitonin might at least hint at an infectious etiology. Also there is no proper consensus as to what constitutes fever.

Non-fever hyperthermia is failure of heat regulation with intact setpoint, e.g. in exsiccosis. Typically, antipyretics are ineffective in pure hyperthermia.

Fever control in the ICU has been studied, if not extensively, and never been shown to be helpful. Most recently, Acetaminophen was not effectively in improving anything (Young NEJM 2015). It may be harmful, especially in septic patients (see Schulman 2005 and Lee 2012).

Central fever

(see this 2016 review on the subject) is always suspected in neuro patients, but hard to prove.

Pathophysiology, it is due to damage to the hypothalamus or contact of this structure to blood 0r pus (this can be reproduced in animals). In brain injury, diffuse axonal damage and frontal lesions indicate shear stress on the hypothalamus and correlate with central fever.

Clinically, central fever might have less diaphoresis and tachycardia, but this is not very specific. The diagnosis relies on exclusion of other infectious and inflammatory causes. The literature (Predicting central fever in NICU, Hocker 2013) says

The combination of negative cultures; absence of infiltrate on chest radiographs; diagnosis of subarachnoid hemorrhage, intraventricular hemorrhage, or tumor; and onset of fever within 72 hours of admission predicted central fever with a probability of .90.

Therapywise, central fever is harder to treat, so that physical measures and endovascular cooling are often employed. I grew up with the lytic cocktail (blocking every neurotransmitter you know), but there is no proper literature on that.

You should bear in mind that there is another central neurologic complication with fever that complicates severe brain injury, namely paroxysmal sympathetic hyperactivity – this is a chapter on its own.

Stroke and fever

  • Very common: (40-61%) in the first 2d of stroke have elevated temperatures, depending on the definition
  • Very bad: Raised temperature correlates with bad outcome, both in animal experiments (40° x 3h leads to 3 times the stroke volume) and patients (e.g., Greer 2008).
  • Early is worse: Stroke is more vulnerable to fever in the first 24 hours – it accelerates the conversion of penumbra to stroke and all bad pathophysiologic cascades (apoptosis, inflammatory).
  • Can be controlled: Fever control is feasible in principle and regarded as one of the active components of stroke unit care.

Temperature management strategies for stroke

  • Hypothermia: Bi 2011, de Georgia 2004, Ictus-L 2006, Ovesen 2013 show no benefit
    EuroHyp-I (ongoing), Ictus 2/3 (terminated; no results yet) – endovascular methods, no evidence (but very effective)
  • Prophylactic
    • antipyretics: PAIS (den Hertog 2009), PISA (Dippel 2003) – only modest effect on temperature, no benefit (NRO, survival)
    • antibiotics: EPIAS, PANTHERIS – reduced infection rates, no benefit (NRO, survival)
  • Fever treatment: blankets/air cooling probably not better than drugs, endovascular highly effective – no benefit shown
    QASC trial shows that the combination of controlling fever, dysphagia and glucose is beneficial

Infectious causes of fever

  • Head: meningitis/encephalitis, brain abscess, ventriculitis, sinusitis, dental, HEENT (including epiglottitis)
  • Circulatory: CVC, endocarditis/myocarditis, peripheral cannula, aortitis, mediastinitis
  • Respiratory: pneumonia/bronchitis, empyema, VAP
  • GI: esophagitis, pancreatitis, diverticulitis, rectal/anal abscess, C. diff
  • Urogenital: prostatitis, pyelonephritis, cystitis, PID
  • Hematological: malaria, HIV
  • Integument: Osteomyelitis, cellulitis, fasciitis, myositis

Noninfectious causes of fever

  • Vascular: stroke, IVH, ICH, SAH, MI, ischemic bowel, DVT
  • Idiopathic inflammatory: Gout, postoperative, acalculous cholecystitis, pancreatitis, aspiration pneumonitis, GI bleed, ARDS
  • Traumatic: Hematoma, Ulcers
  • Toxic
    • Drug fever: high spiking fever, chills, maybe leucocytosis, eosinophilia; drugs are beta-lactams, PHE, iv contrast
    • Malignant neuroleptic syndrome, Serotonin syndrome (beware: linezolid, MCP, setrons), malignant hyperthermia
  • Autoimmune: vasculitis, hemolysis, transplant rejection, transfusion
  • Psychiatric: Withdrawal
  • Neoplastic: renal cell CA, tumor lysis, lymphoma, leucemia
  • Endocrine: Ovulation, Thyroiditis, Thyreotoxicosis, adrenal insufficiency


Get a grip!

Not a HaNDL but a bavarian HeNDL

When a disease is discovered nowadays, it needs to be assigned a proper acronym – see CLIPPERS, MELAS, CADASIL. If we were living in the good ole eponymic days of, say, Steele-Richardson-Olszewski, the HaNDL syndrome would be named Swanson-Bartleson-Whisnant – the authors of a 1980s Neurology paper on the condition we covered in our rounds today. Or better: by Stigler’s law it should be named Berg-Williams-Syndrome after the 1995 Neurology article that coined the acronym HaNDL.

By all we know about the inflammatory pathophysiology of migraine, an increase in frequency and intensity of migraine auras should be able to produce a pleocytosis, but this is not the explanation for HaNDL, for it should enjoy all the epidemiologic characteristics of migraine then. And it doesn’t.

It is men of middle age (40-70, not young women) with only rarely (slightly more than chance predicts) any migraine in their history, who – sometimes after a preceding viral illness – suffer a series of episodes over days to weeks that resemble aura (except: less visual symptoms, more aphasia, more sensorimotor disturbances) in their development and migratory nature, but take way too long (a few hours rather than 10-60 minutes), accompanied or followed by headaches that resemble migraine with slightly less phobias (osmo-, kineto-, photo-, phonophobia). The usual workup (CT, MRI, labs) is negative, but there is a lymphocytotic pleocytosis of > 15/µl and often a raised CSF opening pressure.

Of course, as in any case of focal symptoms plus pleocytosis (aka encephalitis), we send off the standard microbiology tests (HIV, TPHA, borreliosis, PCR for HSV, VZV), start acyclovir and maybe ceftriaxone at once and wait until everything comes back negative. Then we are left with the hopes of a spontaneously resolving syndrome – by definition it should take weeks or months to clear.

In my experience, the usual migraine therapy (iv high dose NSAIDs = metamizol or ASS, plus antiemetics – MCP or dimenhydrinate) covers each episode but does not prevent the next. Steroids might, but don’t last long enough. I usually treat with spreading depression drugs (valproate, topiramate) and hope for the best.

The disease certainly is underrecognized, being replaced by “a minor encephalitis”. There should be some studies of  autoimmune mechanisms and antibodies, but I know of no proper results yet. So, if you are faced with your next HaNDL why not send of an experimental panel?




First described in 1883, the concept of watershed strokes was further developed pathophysiologically in the 50s and 60s. (There is a proud  article in Stroke this week, discussing the  history of the concept.)


Several terms are used in the literature: border-zone stroke, watershed stroke, misery perfusion, Letzte Wiese. Watershed is probably the best term, as it describes the idea that the land most distal to two supplying rivers suffers from even slight variations in flow in either. I personally apply the name Letzte Wiese only in specific cases – it captures an area  insufficiently supplied by just one vessel and thus can be applied only to internal border zone strokes.


For watershed strokes you need either quite severe hypoperfusion (as in hemorrhagic shock) or only minor hypoperfusion but at least one severely stenosed vessel.

  • The most frequent stenosis affects the proximal ICA, leading to the ACA/MCA and PCA/ACA border zones, as well as (sometimes) strokes in the MCA internal border zone.
  • High grade MCA stenosis can lead to watershed strokes in the internal border zone along and above the lateral ventricles (rosary pattern). In this case the region between the supplied region of the deep penetrating endarteries (mainly basal ganglia) and the small branches of the MCA main branches (which enter the brain from the cortex down) suffers, which amounts to the white matter in the centrum semiovale.
  • Finally the cerebellum knows watershed zones between the 3 feeding vessels, but this is not of practical relevance because treatment is similar to embolic strokes.

ICA stenosis

  • In chronic near occlusion of the ICA, the borderzone region can move if you give it enough time, with the PCA/MCA region moving forward and the ACA/MCA region backward.
  • To complicate matters further, the borderzones are variable depending on the localization of the stenosis and the integrity of the ECA collateral as well as the Circle of Willis (e.g., if A1 or the anterior communicating artery is hypoplastic or the PCA has the fetal variant).
  • In my experience you need at least 2 patent collaterals (out of ECA, ACA, PCA) to ensure hemodynamic stability even in near occlusion.
  • In the last years we learnt more about degenerative distal ICA stenosis just below the carotid T which is not well collateralized via the ECA pathway – this region unfortunately is not well imaged with CTA due to calcification-related artifacts, being  better amenable to duplex ultrasound and MRA.
  • Similar problems can arise with dissections extending to the intracranial sections of the ICA.
  • In very slowly progressive combined distal ICA and MCA stenosis (degenerative, vasculitis, Moya Moya disease) a web of tiny collaterals can form (Moya Moya picture), which has its own intricate pathophysiology.

Pathophysiology of hypoperfusion

Local hypoperfusion can be graded as follows:

  • Grade I: reduced CBF, enhanced CBV, functionally intact or only slightly compromised, near normal oxygen extraction, reduced vasodilatatory reserve
  • Grade II: severely reduced CBF, reduced CBV, reduced function, no or negative local vasodilatatory reserve (the latter is called the reverse Robin Hood phenomenon)

Practical management

  • When faced with an imaging pattern of watershed strokes, duplex ultrasound and angiography (CTA, MRA or even conventional angiography) are urgent to get as much information as possible about the flow patterns and the collateral situation.
  • Perfusion imaging: Severe proximal stenoses leads to difficulties in interpreting perfusion imaging, but this can be used to try to differentiate between grade I and II hemodynamic compromise.
  • To judge how imminent the danger is, functional ultrasound of the MCA (using CO2, apnea or – easier – acetazolamide 1g) is used.
  • If  in doubt, I recommend a trial of therapeutic hypertension (usually with 25-50-100µg Noradrenaline, only with intact coronaries!) to see whether the neurologic deficit fluctuates with blood pressure.
  • In this case, an emergency revascularization is necessary and without alternative. To bridge the time to surgery or stenting, you can use continuous therapeutic hypertension, aiming for an RR of > 180 or 200 mmHg.
  • Sensitivity to blood pressure drops: Quite often the reverse happens – someone accidentally treats an impressively high RR of 220 mmHg (which might actually be due to the brains own reaction to hypoperfusion) with an iv bolus of labetalol or urapidil and the patient deteriorates. If this happens, quickly counteract your medication (Noradrenaline again) and due your vascular studies.
  • Remember that patients with severe misery perfusion, the danger of hyperperfusion syndrome after revascularization is quite real and this is difficult to treat.