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

 

Enhanced Recover After Surgery (ERAS) for Neuro-oncologic Surgeries

Enhanced Recovery After Surgery (ERAS) was originally conceptualized to decrease morbidity after colorectal surgery and has since been expanded to encompass other abdominopelvic surgeries.  A review article from Journal of Clinical Neuroscience (2015) applied the ERAS concept to elective craniotomies for tumor resections to facilitate hospital discharge for cancer patients, expedite subsequent chemoradiothrapy and improve patient outcome.

The guidelines proposed include:

  1. Pre-operative
    1. Patients should routinely be counselled on what to expect from surgery. (Low, Strong)
    2. Patients should abstain from alcohol and smoking 1 month prior to surgery (Mod, Strong)
    3. Patients should be given enteral nutrition preoperatively. (Mod, Strong)
    4. Patients may benefit from immunonutrition perioperatively. (Mod, Weak)
    5. Patient should be encouraged to load with carbohydrates perioperatively.*  (Low, Strong)

*Perioperative oral CHO loading up to 2 hours prior to surgery has been shown to attenuate insulin resistance and improve subjective feelings of hunger, thirst, and post-operative fatigue compared with fasting.  As CHO beverages are a clear liquid, perioperative CHO loading should be encouraged.

  1. Intra-operative 
    1. Surgeon should minimize scalp shaving. (Mod, Weak)
    2. Cefazolin should be given within 1 hour prior to skin incision.  For patients with MRSA, vancomycin should be initiated 1 hour prior to skin incision. (High, Strong)
    3. Surgeon should utilize scalp in filtration and scalp blocks for craniotomies. (Mod, Strong)
    4. There is no evidence that short-acting anesthetics are superior to longer acting anesthetics, nor TIVA to pure inhalational anesthetics.
    5.  Minimally invasive surgery may improve patient recovery and satisfaction. (Very low, Weak)
  2. Post-operative
    1. Gabapentin / pregabalin / tramadol have side effect profiles that are unfavorable for craniotomy. (Low, Weak)
    2. Low evidence for efficacy of intravenous acetaminophen, but side effect profile is favorable.  (Mod, Strong)
    3. There may be a role for limited dosing of COX-2 inhibitors and flupirtine pending further research.  (Low, Weak)
    4. Routine serotonin receptor antagonists and dexamethasone is recommended for PONV.  (High, Strong)
    5. Aprepitant should be reserved for patients at high risk of PONV due to higher cost and limited effectiveness.  TEAS (transcutaneous electrical acupoint stimulation) requires further study.  (Low, Weak)
    6. Scopolamine and promethazine side effect profiles make them undesirable as first-line nausea meds.  (Low, Weak)
    7. Avoid hypothermia.  (High, Strong)
    8. Remove Foley on posteroperative day 1 or as early as feasible.  (Mod, Strong)
    9. Post-operative TPN not needed except for patients in prolonged comatose state.  (Mod, Strong)
    10. Encourage early mobilization.  (High, Strong)
  3. Others:
    1. Patients should use graduated compression stockings and intermittent pneumatic compression to prevent VTE.  Routine use of anticoagulants is not recommended. (High, Strong)
    2. Audit measure routinely.  (Mod, Strong)

 

Capture

Capture2

Sample Neurosurgery-ERAS Guideline given to patients from Penn medicine: ERAS Neurosurgery

Reference:

Hagan, K., Bhavsar, S., Raza, S., Arnold, B., Arunkumar, R., Dang, A., Gottumukkala, V., Popat, K., Pratt, G., Rahlfs, T. and Cata, J. (2016). Enhanced recovery after surgery for oncological craniotomies. Journal of Clinical Neuroscience, 24, pp.10-16.

 

Algorithm for Treatment of Cerebral Venous Thrombosis (CVT)

An algorithm for the diagnosis and management of CVT:

Capture.JPG

CTV, CT venography; CVT, cerebral venous thrombosis; ICH, intracerebral
hemorrhage; LMWH, low molecular weight heparin; MRV, magnetic resonance venography; PRES, posterior reversible encephalopathy syndrome; UHF,
unfractionated heparin.

 

Table 1 Major risk factors and conditions associated with CVT
Infection

  • INFECTION:
    • Paranasal sinusitis
    • Intracranial infections: abscess, meningitis
    • Trauma Head trauma, neurosurgical operations
    • Internal jugular catheter
  • MEDICAL / SURGICAL CONDITIONS
    • Dehydration
    • Pregnancy and puerperium
    • Coagulation disorders: factor V Leiden, protein C / S deficiency, antithrombin III deficiency, hyperhomocysteinemia, APAS
    • Hematologic disorders: polycythemia, sickle cell disease, TTP, polycythemia, PNH
    • Malignancies, inflammatory bowel disease, nephrotic syndrome, liver cirrhosis, collagen vascular disease including SLE, Wegener’s granulomatosis and Behçet syndrome
    • Previous surgical procedures
  • MEDICATION
    • Oral contraceptives, hormone replacement therapy,  L-asparagenase, corticosteroid

 

Table 3 Clinical presentations of CVT:

  • Symptoms
    • Headache
    • Double or blurred vision
    • Altered consciousness
    • Seizure
    • Behavioral symptoms (delirium, amnesia, mutism)
  • Signs
    • Papilledema
    • Focal neurologic deficit
    • Cranial nerve palsy
    • Nystagmus

 

Society of Neurointerventional Surgery (SNIS) Recommendations:

Imaging
► A combination of MRI/MRV or CT/CTV studies should be performed in patients with suspected CVT (class I; level of evidence C).
► DSA as a diagnostic modality is indicated in cases of suspected CVT when the diagnosis of CVT cannot be reliabl established with non-invasive imaging alone (class IIa; level of evidence C).

Medical and surgical treatment
► Anticoagulation with unfractionated heparin or low molecular weight heparin is reasonable in patients with CVT (class IIa; level of evidence C).
► Decompressive craniectomy may be considered in patients with large parenchymal lesions causing herniation or intractable intracranial hypertension (class IIb; level of evidence C).

Endovascular therapy
► Endovascular therapy may be considered in patients with clinical deterioration despite anticoagulation, or with severe neurological deficits or coma (class IIb; level of evidence C). The duration of anticoagulation therapy before declaring it to be a ‘failure’ and proceeding with endovascular therapy is unknown.
► There is insufficient evidence to determine which endovascular approach and device provides the optimal restoration of venous outflow in CVT. In many cases, a variety of treatment approaches is required to establish sinus patency.

 

Radiologic Findings in CVT:

  1.  noncontrast CT – hyperdensity of occluded sinuses + cerebral edema +/- ICH
  2. contrast CT – empty delta sign, HU>70% highly specific for acute CVT
  3. MRI – T2 hypointensity in acute CVT, T1 and T2 hyperintensity in subacute CVT

 

 

References

Lee, S., Mokin, M., Hetts, S., Fifi, J., Bousser, M. and Fraser, J. (2018). Current endovascular strategies for cerebral venous thrombosis: report of the SNIS Standards and Guidelines Committee. Journal of NeuroInterventional Surgery, 10(8), pp.803-810.

 

Stress Dose Steroids

WHEN IS STRESS DOSE STEROIDS INDICATED?

  • depends on history of steroid intake and likelihood of HPA supression + type and duration of surgery
  • NONSUPPRESSED HPA AXIS: 
    • < 3 weeks of steroids at any dose
    • prednisone <5mg/daily for any duration
    • prednisone <10mg every other day
    • PLAN:  continue same regimen perioperatively; no need for cosyntropin test or stress dose steroids
  • SUPPRESSED HPA AXIS
    • prednisone >20mg/day x 3 weeks or more OR Cushingoid appearance
    • PLAN:
      • give stress dose steroids based on type and duration of surgery (see below)
  • INTERMEDIATE HPA SUPPRESSION (Unknown HPA Axis suppression, previous 3 or more intraarticular or spinal steroid injections within 3 mos prior to suregery)
    • PLAN
      • evaluate HPA axis 
        • check AM cortisol (8a.m.) after 24h off steroids
        • if <5 ug/dL – likely suppressed axis; give stress dose steroids
        • if >10 ug/dL – likely no supression; continue current dose on day of surgery
        • if 5-10 ug/dL – ACTH stim test or empiric stress dose steroids
      • ACTH stim test (standard is 250 ug):
        • if serum cortisol <18 ug/dL 30 mins after ACTH – give stress dose steroids
        • if >serum cortisol >18 ug/dL 30 mins after ACTH – no stress dose steroids

 

STEROIDS BASED ON TYPE AND DURATION OF SURGERY

MINOR PROCEDURES / LOCAL ANESTHESIA – stress dose not necessary, take AM steroids

MODERATE SURGICAL STRESS: (eg. LE revascularization, total joint replacement)

  1. take AM steroids
  2. hydrocortisone 50mg IV prior to procedure, 25mg IV q8h x 24h
  3. resums usual dose after

MAJOR SURGICAL STRESS (e.g open heart surgery, proctocolectomy, esophagogastrectomy)

  1. take AM steroids
  2. hydrocortisone 100mg IV before induction of anesthesia
  3. hydrocortisone 50mg q8h x 24h
  4. taper by half per day to maintenance dose

 

 

 

Reference:

Uptodate.com. (2018). UpToDate. [online] Available at: http://www.uptodate.com/contents/the-management-of-the-surgical-patient-taking-glucocorticoids?search=stress+dose+steroids&source=search_result&selectedTitle=1~60#H6 [Accessed 25 Mar. 2018].