Glibenclamide for Brain Edema

PATHOPHYSIOLOGY OF CEREBRAL EDEMA IN STROKE:

  • Following ischemic insult, SUR1-TRPM4 ion channel expressed in all cells of the neurovascular unit.
  • Early stages of ischemia, channel upregulation occurs at the luminal and abluminal surfaces of the vascular endothelium, mediating an ionic gradient from the intraluminal space to the interstitial space.
  • Water transported from vasculature into the parenchyma.
  • Formation of ionic gradient followed by or accompanied by breakdown of the BBB.
  • Capillary structure is maintained, preventing extravasated of cells, while vasculature becomes open to water movement and movement of macromolecules s.a. Immunoglobulin / albumin.
  • Opening facilitates osmotic and hydrostatic movement of water into brain.
  • Tight junctions between vascular endothelial cells degraded by MMP9, which further facilitates fluid movement into the brain.

MECHANISM OF ACTION OF GLIBENCLAMIDE

  • Glibenclamide is an anti-edema drug.
  • Glibenclamide blocks the activity of the SUR1-TRPM4 ion channel.
  • This channel is upregulated in the CNS only after ischemia / trauma.
  • Glibenclamide blocks this cascade, protects the neurovascular unit.
  • First impact is on the capillary endothelium, rather than neurons.
  • Glibenclamide does not cross the uninjured BBB, only the channels up-regulated in the vascular endothelium are relevant until such time as the BBB is disrupted.

Reference:

Jacobson, S., MacAllister, T. and Geliebter, D., 2020. Found in translation: The rationale behind the early development of glibenclamide in large hemispheric infarction. Neuroscience Letters, 716, p.134672.

Headache After SAH

Headache after SAH increases in intensity during first 7d after onset.

Mechanism:

  • factors that contribute to vasopasm may also lead to headache
  • chemical irritation of blood on meninges and subarachnoid space can cause pain
  • infiltration of immune cells, immune activation and inflammatory cytokines contributes to pain
  • alterations in brain perfusion from vasopasm may also be a factor

 

Treatment:

  • Fioricet largely ineffective, ?associated with early vasospasm
  • In SAH patients, elevated Mg levels associated with less severe headache, – IV magnesium therapy may provide relief for SAH patients?
    • Magnesium is a non-competitive antagonist of voltage-dependent calcium channels and NMDA receptor.  Blocking of NMDA receptor is involved in pain modulation – prevents induction of central pain sensitisation. 
    • The effect of magnesium on headache after SAH is unknown. 
    • Most studies use dose of 1-2G IV bolus, in the study referenced below, higher daily dose (16G MgSO4 for a sustained period – nonbolus) was given. 
    • Diarrhea is a common side effect.

 

AP41 cocktail:

  1. Fioricet 1 q4h
  2. tramadol 100 q6h
  3. valproate 500 IV q8h x3d
  4. metoclopramide 5-10mg q6h x 3d
  5. Mg 2G IV once

*monitor QT interval

 

References

Dorhout Mees, S., Bertens, D., van der Worp, H., Rinkel, G., & van den Bergh, W. (2009). Magnesium and headache after aneurysmal subarachnoid haemorrhage. Journal Of Neurology, Neurosurgery & Psychiatry81(5), 490-493. doi: 10.1136/jnnp.2009.181404

Swope, R., Glover, K., Gokun, Y., Fraser, J., & Cook, A. (2014). Evaluation of headache severity after aneurysmal subarachnoid hemorrhage. Interdisciplinary Neurosurgery1(4), 119-122. doi: 10.1016/j.inat.2014.07.003

Central Fever

Central fever / Paroxysmal Hyperthermic Autonomic Dysregulation

  • commonly associated with closed head injury, hydrocephalus
  • nonsustained episodes of hyperpyrexia, tachycardia , tachypnea, increased blood pressure, increased extensor tone, pupil dilatation, diaphoresis (see related post on sympathetic storming)

Pathophysiology:

  • injury involving hypothalamus
  • neuroimmulogic mechanisms?
  • initial release of cytokines (IL-1, IL-6, TNF-α and IFN-γ), secondary to direct trauma, infection of brain, inflammatory stimulation and increased ICP after acute brian injury activate COX-2 pathways in periventricular cells and production of PGE
  • stressed cells after brain injury synthesize heath shock proteins in coordinated response to tissue injury
  • glutamate and nitric oxide release caused by autonomic dysregulation of the brianstem

Rule out:

  • infection
  • epileptic disorders
  • pheochromocytoma
  • NMS
  • increased ICP
  • hydrocephalus
  • Cushing’s syndrome
  • thyrotoxicosis
  • DVT

Treatment:

  • The current effective drugs are
    • propranolol, opioid, clonidine, bromocriptine, chlorpromazine, dantrolene  
    • Propranolol 20 to 30 mg every 6 hours
  • Stereotactic surgery is sometimes considered when these drugs are ineffective

 

Reference:

Meythaler, J., & Stinson, A. (1994). Fever of central origin in traumatic brain injury controlled with propranolol. Archives Of Physical Medicine And Rehabilitation75(7), 816-818. doi: 10.1016/0003-9993(94)90143-0

Oh, S., Hong, Y., & Song, E. (2007). Paroxysmal Autonomic Dysregulation with Fever that was Controlled by Propranolol in a Brain Neoplasm Patient. The Korean Journal Of Internal Medicine22(1), 51. doi: 10.3904/kjim.2007.22.1.51

 

 

Unruptured Intracranial Aneurysm Treatment Score

UIATS = Unruptured Intracranial Aneurysm Treatment Score

  • quantifies 29 key factors related to patient, aneurysm and treatment characteristics involved in clinical decision-making in management of unruptured aneurysm
  • 2 scores generated – 1 favoring repair and the other favoring conservative management.
  • For a score difference with >3 points, higher score suggests the type of treatment
  • For a score difference with <=2 points, no definitive recommendations can be made

 

 

Reference:

Mayer, T., Etminan, N., Morita, A., & Juvela, S. (2016). The unruptured intracranial aneurysm treatment score: A multidisciplinary consensusAuthor Response. Neurology86(8), 792.2-793. doi: 10.1212/01.wnl.0000481228.68055.71

 

 

 

 

Hypoglycorrhachia Differential Diagnosis

Common and Uncommon Etiologies of Hypoglycorrhachia in the LiteratureCapture

ETIOLOGIES COMMONLY ASSOCIATED WITH HYPOGLYCORRHACHIA

  • Bacterial meningitis (including atypical bacteria like nocardia and brucella)
  • Fungal meningitis
  • Mycobacterial (tuberculous meningitis)
  • Amebic meningoencephalitis
  • CMV-associated progressive polyradiculopathy or meningoencephalitis
  • Carcinomatous meningitis
  • GLUT 1-deficiency syndrome
  • Leukemia/lymphoma with CNS involvement
  • Subarachnoid hemorrhage

 

ETIOLOGIES UNCOMMONLY ASSOCIATED WITH HYPOGLYCORRHACHIA

  • Syphilitic meningitis
  • Lyme meningitis
  • Viral meningitis
  • Neurocysticercosis5
  • CNS toxoplasmosis
  • Cholesterol-induced leptomeningitis secondary to Currarino syndrome
  • Neurosarcoidosis
  • Rheumatoid meningitis
  • Systemic lupus erythematosus with CNS involvement
  • Neuro-Behcet’s Disease
  • Dermoid cyst
  • Granulomatous angiitis of the central nervous system
  • Malignant atrophic papulosis

 

Etiologies reported to cause severe hypoglycorrhachia, (CSF glu ≤10 mg/dL)

  • Bacterial meningitis (including atypical bacteria like nocardia and brucella) *
  • Fungal meningitis*
  • Mycobacterial (tuberculous meningitis)*
  • Carcinomatous meningitis*
  • Leukemia/lymphoma with CNS involvement*
  • Subarachnoid hemorrhage*
  • Lyme meningitis*
  • Neurocysticercosis5*
  • Cholesterol-induced leptomeningitis secondary to Currarino syndrome*
  • Neurosarcoidosis*
  • Dermoid cyst*

 

Frequency of Different Known Diagnoses Seen in Patients with Hypoglycorrhachia

  1. All Patients

1

2. HIV-Infected Patients

2

3. Patients with History of Neurosurgery

3

4. Patients without HIV or Neurosurgical History

4

 

Reference:

Chow, E., & Troy, S. (2014). The Differential Diagnosis of Hypoglycorrhachia in Adult Patients. The American Journal Of The Medical Sciences348(3), 186-190. doi: 10.1097/maj.0000000000000217

 

Blood Pressure Augmentation in DCI

HIMALAIA Study – Netherlands. The only RCT looking at efficacy of BP augmentation in DCI in increasing cerebral blood flow (via CT perfusion).  Small n, negative study.

Tey article – XeCt to measure regional CBF, at onset of DCI suspicion, 5 days of induced HTN, hypervolemia, hemodilution. Compared XeCT before and after treatment and showed increase in regional CBF in worst vascular territories from 19 to 227ml/100g/min, significant reduction of regions with CBF <20ml/100g/min from 26 to 10%.

Indications:

  1. decrease in GCS >=1
  2. new focal deficits
  3. other etiologies excluded:
    1. worsening HCP
    2. recurrent bleeding
    3. epilepsy
    4. infectious disease
    5. hypoglycemia
    6. hyponatremia
    7. metabolic enceph from renal or liver failure

 

Baseline echo:  cardiomyopathy is a contraindication

Drug of choice:  Induce HTN with norepinephrine? based on reference below (we usually use phenylephrine)

End points:

  1. improvement of neurologic deficits
  2. occurrence of complication
  3. MAP 130 mm Hg
  4. SBP 230 mm Hg

 

Risks of Induced HTN:

  1.  line placement risks
  2. vasopressor risks
  3. can induce PRES, neurologic deterioration

 

Literature does not support the use of induced HTN, but how can we ignore bedside observations of patients who clinically improve with induced HTN?

Critique:

  1. Uses surrogate physiologic endpoints (CBF / cerebral o2 delivery). Are we looking at the right endpoint?  CBF correlates with cerebral O2 delivery assuming that other factors are constant (cerebral metabolism, arterial O2 content, partial pressure of O2 and CO2).
  2. Different patients have varied responses to induced HTN.  Induced HTN increases CBF only if cerebral autoregulation is distupted.

 

Dr. Diringer’s Advice: use induced HTN in a thoughtful and individualized manner.  Trial of induced HTN at onset of DCI.  If patient improves, continue.  If no change, back off and explore alternative treatments. If patient exam is poor (no followable exam), answer less clear but prolonged extreme elevations should be avoided.

References:

Gathier, C., Dankbaar, J., van der Jagt, M., Verweij, B., Oldenbeuving, A., Rinkel, G., van den Bergh, W. and Slooter, A. (2015). Effects of Induced Hypertension on Cerebral Perfusion in Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage. Stroke, 46(11), pp.3277-3281.

Diringer, M.  Editorial. Hemodynamic Therapy for Delayed Cerebral Ischemia in SAH.  Neurocritical Care Journal.  Pre-print.