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.
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 increases in intensity during first 7d after onset.
- 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
- 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.
- Fioricet 1 q4h
- tramadol 100 q6h
- valproate 500 IV q8h x3d
- metoclopramide 5-10mg q6h x 3d
- Mg 2G IV once
*monitor QT interval
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 & Psychiatry, 81(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 Neurosurgery, 1(4), 119-122. doi: 10.1016/j.inat.2014.07.003
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)
- 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
- epileptic disorders
- increased ICP
- Cushing’s syndrome
- 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
Meythaler, J., & Stinson, A. (1994). Fever of central origin in traumatic brain injury controlled with propranolol. Archives Of Physical Medicine And Rehabilitation, 75(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 Medicine, 22(1), 51. doi: 10.3904/kjim.2007.22.1.51
Northwell Health COVID19 and Guidance on Management of Antithrombotic Therapy; Dr. Alex C. Spyropoulos System Director – Anticoagulation and Clinical Thrombosis Services; Graphic Editor: Dr. Rachel-Maria Brown, Director – Inpatient Cardiac Services
DETECTION OF VIRAL RNA (RT-PCR tests)
- RT PCR targets the following genes
- env – envelope
- N – nucleocapsid
- S – spike
- RdRp – RNA-dependent RNA polymerase
- ORF1 genes
- Cycle threshold
- number of replication cycles required to produced a fluorescent signal
- lower Ct values represent higher viral RNA loads
- Ct value <40 clinically reported as PCR positive
- Ct values in severely ill patients are lower than mild cases
- (+) PCR result reflects only detection of the viral RNA, not necessarily indicate presence of viable virus
- RT-PCR positivity
- BAL specimen (93%)
- sputum (72%)
- nasal swab (63%)
- pharyngeal swab (32%)
- Specificity is 100%
- RT-PCR positivity
DETECTION OF ANTIBODIES
- most sensitive and earliest serological maker is TOTAL ANTIBODIES, which increase from 2nd week of symptom onset
- IgM and IgG ELISA have been found (+) as early as Day 4 of symptom onset
- higher levels in second and third week
- IgG and IgM seroconversion occurred in all patients between third and fourth week
- IgM begins to decline and reach lower levels by week 5 and disappears by week 7
- IgG persists beyond 7 weeks
- >95% specificity for diagnosis of COVID-19
- majority of Ab are produced against NC (most abundant protein of the virus), tests to detect Ab would be most sensitive
- receptor-binding domain of S (RBD-S) protein is the host attachment protein, would be more specific and expected to be neutralizing
Sethuraman, N., Jeremiah, S., & Ryo, A. (2020). Interpreting Diagnostic Tests for SARS-CoV-2. JAMA. doi: 10.1001/jama.2020.8259
Holmes, K. (2003). SARS-Associated Coronavirus. New England Journal Of Medicine, 348(20), 1948-1951. doi: 10.1056/nejmp030078
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
Mayer, T., Etminan, N., Morita, A., & Juvela, S. (2016). The unruptured intracranial aneurysm treatment score: A multidisciplinary consensusAuthor Response. Neurology, 86(8), 792.2-793. doi: 10.1212/01.wnl.0000481228.68055.71
Common and Uncommon Etiologies of Hypoglycorrhachia in the Literature
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
- CNS toxoplasmosis
- Cholesterol-induced leptomeningitis secondary to Currarino syndrome
- 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*
- Cholesterol-induced leptomeningitis secondary to Currarino syndrome*
- Dermoid cyst*
Frequency of Different Known Diagnoses Seen in Patients with Hypoglycorrhachia
- All Patients
2. HIV-Infected Patients
3. Patients with History of Neurosurgery
4. Patients without HIV or Neurosurgical History
Chow, E., & Troy, S. (2014). The Differential Diagnosis of Hypoglycorrhachia in Adult Patients. The American Journal Of The Medical Sciences, 348(3), 186-190. doi: 10.1097/maj.0000000000000217