Thiopental

Thiopental

Thiopental (Pentothal®)


Thiopental administration has been described as an effective method to prevent postoperative neurological deficits in several animal studies 1) 2) 3) 4) 5)

Here are some key points about the use of thiopental in neurosurgery:

Induction of Anesthesia: Thiopental is often used as an induction agent to rapidly induce anesthesia in patients undergoing neurosurgical procedures. Its rapid onset of action makes it suitable for this purpose.

Sedation and Amnesia: Thiopental induces a state of sedation, amnesia, and unconsciousness, which is important for ensuring that patients do not experience pain or awareness during surgery.

Short Duration: One of the advantages of thiopental is its short duration of action. This allows for precise control of anesthesia depth and a quick recovery once the drug is discontinued.

Neuroprotective Properties: Thiopental has been investigated for its potential neuroprotective properties in the context of neurosurgery. It may help reduce the metabolic demands of the brain during surgery, which could be beneficial in cases where brain tissue needs to be protected.

Control of Intracranial Pressure (ICP): Thiopental can temporarily lower intracranial pressure (ICP), which can be important in neurosurgical procedures involving brain tumors or traumatic brain injury. By reducing ICP, it may provide a safer surgical environment.

Barbiturate Coma: In some cases of severe traumatic brain injury or refractory intracranial hypertension, thiopental has been used to induce a controlled barbiturate coma. This coma state is maintained for a specific duration to protect the brain from further damage and reduce ICP.

Administration: Thiopental is administered intravenously, typically as a rapid bolus injection. The dosage and administration rate are carefully controlled by an anesthesiologist to achieve the desired level of anesthesia.

Side Effects: Like all anesthetic drugs, thiopental can have side effects, including respiratory depression, hypotension (low blood pressure), and a risk of allergic reactions. These side effects are closely monitored during surgery.

Availability: The availability of thiopental may vary by region, and its use may be subject to regulatory restrictions. In some places, it has become less commonly used due to concerns about the misuse and availability of lethal injection

May be useful when a rapidly acting barbiturate is needed (e.g. intra-op) or when large doses of pentobarbital are not available. One of many protocols is as follows (note: thiopental has not been as well studied for this indication, but is theoretically similar to pentobarbital):

1. Loading dose: thiopental 5 mg/kg (range: 3–5) IV over 10 minutes → transient burst suppression (< 10 minutes) and blood thiopental levels of 10–30 mcg/ml. Higher doses (≈ 35 mg/kg) have been used in the absence of hypothermia to produce longer-duration burst suppression for cardiopulmonary bypass

2. Follow with continuous infusion of 5 mg/kg/hr (range: 3–5) for 24 hours

3. may need to rebolus with 2.5 mg/kg as needed for ICP control

4. After 24 hours, fat stores become saturated, reduce infusion to 2.5 mg/kg/hr

5. titrate to control ICP or use EEG to monitor for electrocerebral silence

6. “therapeutic” serum level: 6–8.5 mg/dl


Chemically, propofol is not related to barbiturates and has largely replaced sodium thiopental (Pentothal) for induction of anesthesia because recovery from propofol is more rapid and “clear” when compared with thiopental. Propofol is not considered an analgesic, so opioids such as fentanyl may be combined with propofol to alleviate pain.


Thiopental and decompressive craniectomy are important integrated last-tier treatment options in aneurysmal subarachnoid hemorrhage, but careful patient selection is needed due to the risk of saving many patients a state of suffering 6).


A study showed that thiopental was associated with a lower risk of neurological complications after clipping of Unruptured Intracranial Aneurysm 7).

What is the primary purpose of using Thiopental in neurosurgery? a) Pain relief b) Rapid induction of anesthesia c) Prolonged sedation d) Reducing blood pressure

Why is Thiopental chosen for induction in neurosurgery? a) It provides prolonged anesthesia. b) It has a rapid onset of action. c) It reduces intracranial pressure. d) It is an effective analgesic.

Which of the following is NOT a characteristic of Thiopental? a) Short duration of action b) Neuroprotective properties c) Rapid bolus injection d) Long-lasting sedation

In what situations might Thiopental be used to induce a controlled barbiturate coma? a) Routine neurosurgical procedures b) Cases of severe traumatic brain injury c) During outpatient surgeries d) For postoperative pain management

How is Thiopental typically administered? a) Orally b) Intramuscularly c) Intravenously d) Subcutaneously

What is the recommended therapeutic serum level of Thiopental? a) 1-2 mg/dl b) 6-8.5 mg/dl c) 20-30 mcg/ml d) 50-60 mg/dl

Why has Propofol largely replaced Thiopental for induction of anesthesia? a) Propofol is cheaper. b) Propofol has a shorter duration of action. c) Propofol is more effective at reducing intracranial pressure. d) Propofol has a faster recovery time.

What is a potential risk associated with using Thiopental in neurosurgery? a) Rapid recovery b) Allergic reactions c) Hypertension d) Analgesia

When might Thiopental and decompressive craniectomy be considered as treatment options in aneurysmal subarachnoid hemorrhage? a) As a first-line treatment b) As a second-line treatment c) As a last-tier treatment d) Only in cases of minor bleeding

What did a study suggest about the use of Thiopental in clipping of Unruptured Intracranial Aneurysm? a) It had no impact on neurological complications. b) It increased the risk of complications. c) It was associated with a lower risk of neurological complications. d) It prolonged surgical procedures.

Answers:

b) Rapid induction of anesthesia b) It has a rapid onset of action. d) Long-lasting sedation b) Cases of severe traumatic brain injury c) Intravenously b) 6-8.5 mg/dl d) Propofol has a faster recovery time. b) Allergic reactions c) As a last-tier treatment c) It was associated with a lower risk of neurological complications.


1)

Michenfelder J.D. The Interdependency of Cerebral Functional and Metabolic Effects Following Massive Doses of Thiopental in the Dog. Anesthesiology. 1974;41:231–236. doi: 10.1097/00000542-197409000-00004.
2)

Drummond J.C., Cole D.J., Patel P.M., Reynolds L.W. Focal cerebral ischemia during anesthesia with etomidate, isoflurane, or thiopental: A comparison of the extent of cerebral injury. Neurosurgery. 1995;37:742–748. doi: 10.1227/00006123-199510000-00019.
3)

Kofke W.A., Nemoto E.M., Hossmann K.A., Taylor F., Kessler P.D., Stezoski S.W. Brain blood flow and metabolism after global ischemia and post-insult thiopental therapy in monkeys. Stroke. 1979;10:554–560. doi: 10.1161/01.STR.10.5.554.
4)

Musch T.I., Pelligrino D.A., Dempsey J.A. Effects of prolonged N2O and barbiturate anaesthesia on brain metabolism and pH in the dog. Respir. Physiol. 1980;39:121–131. doi: 10.1016/0034-5687(80)90040-7.
5)

Zarchin N., Guggenheimer-Furman E., Meilin S., Ornstein E., Mayevsky A. Thiopental induced cerebral protection during ischemia in gerbils. Brain Res. 1998;780:230–236. doi: 10.1016/S0006-8993(97)01188-8.
6)

Björk S, Hånell A, Ronne-Engström E, Stenwall A, Velle F, Lewén A, Enblad P, Svedung Wettervik T. Thiopental and decompressive craniectomy as last-tier ICP-treatments in aneurysmal subarachnoid hemorrhage: is functional recovery within reach? Neurosurg Rev. 2023 Sep 7;46(1):231. doi: 10.1007/s10143-023-02138-6. PMID: 37676578.
7)

Kim BG, Jeon YT, Han J, Bae YK, Lee SU, Ryu JH, Koo CH. The Neuroprotective Effect of Thiopental on the Postoperative Neurological Complications in Patients Undergoing Surgical Clipping of Unruptured Intracranial Aneurysm: A Retrospective Analysis. J Clin Med. 2021 Mar 12;10(6):1197. doi: 10.3390/jcm10061197. PMID: 33809302; PMCID: PMC7999640.

Propofol

Propofol

Propofol is a potent intravenous (IV) anesthetic agent used for the induction and maintenance of general anesthesia during surgical procedures and medical interventions. It is one of the most widely used and recognized anesthesia drugs in clinical practice. Here are some key points about propofol:

Induction of Anesthesia: Propofol is often used to rapidly induce anesthesia in patients before surgery or medical procedures. It causes rapid loss of consciousness and a state of general anesthesia.

Maintenance of Anesthesia: In addition to induction, propofol can also be used to maintain anesthesia during surgery. Anesthesia providers can adjust the infusion rate to maintain the desired level of anesthesia.

Rapid Onset and Offset: One of the advantages of propofol is its rapid onset of action, typically within seconds after IV administration. It also has a relatively short duration of action, which allows for a quicker recovery when compared to some other anesthetic agents.

Sedation and Amnesia: Propofol induces a state of sedation, amnesia, and unconsciousness. Patients under the influence of propofol do not feel pain or remember the surgical procedure.

Controlled Infusion: Propofol is administered as a controlled infusion through an IV line. The infusion rate is adjusted to maintain the desired level of anesthesia throughout the procedure.

Side Effects: Common side effects of propofol include respiratory depression, hypotension (low blood pressure), and pain at the injection site. These effects are closely monitored during surgery.

Antiemetic Properties: Propofol has antiemetic (anti-nausea and anti-vomiting) properties, making it useful in preventing postoperative nausea and vomiting.

Propofol-Related Infusion Syndrome (PRIS): In rare cases, prolonged and high-dose use of propofol can lead to a condition called PRIS, which may result in metabolic acidosis, heart and kidney dysfunction, and other serious complications. This is why propofol use is carefully monitored, and its dosage is controlled.

Not an Analgesic: It’s important to note that propofol is not an analgesic (pain reliever). It is typically used in conjunction with analgesic medications such as opioids to manage pain during and after surgery.

Intravenous Administration Only: Propofol is administered exclusively through IV injection. It is not available in oral or other forms.

Rapid Recovery: Due to its short duration of action, patients typically wake up quickly and experience a clear-headed recovery after discontinuation of propofol.

Color and Lipid Emulsion: Propofol is known for its milky white appearance, and it is formulated as a lipid emulsion. This unique formulation contributes to its rapid onset and offset of action.

Special Considerations: Dosage and administration of propofol are tailored to the patient’s age, weight, medical condition, and the type of surgery being performed.

see Agents generally used for induction.



Reduces cerebral metabolismCBF and ICP. Has been described for cerebral protection and for sedation. Short half-life permits rapid awakening which may be useful for awake craniotomy. Not analgesic.

The exact mechanism of action unknown. Short half-life with no active metabolites. May be used for induction and as a continuous infusion during total intravenous anesthesia (TIVA). It causes a dose-dependent decrease in mean arterial blood pressure (MAP) and ICP.

It is more rapidly cleared than and has largely replaced thiopental.


Dexmedetomidine (Precedex®). Alpha 2 adrenergic receptor agonist, used for control of hypertension postoperatively, as well as for its sedating qualities during awake craniotomy either alone or in conjunction with propofol.


Propofol has a mild effect on evoked potential (EP): total anesthesia with propofol causes less EP depression than inhalational agents at the same depth of anesthesia 1).


Propofol (INN, marketed as Diprivan by Fresenius Kabi) is a short-acting, intravenously administered hypnotic/amnestic agent. Its uses include the induction and maintenance of general anesthesia, sedation for mechanically ventilated adults, and procedural sedation. Propofol is also commonly used in veterinary medicine. It is approved for use in more than 50 countries, and generic versions are available.

Chemically, propofol is not related to barbiturates and has largely replaced sodium thiopental (Pentothal) for induction of anesthesia because recovery from propofol is more rapid and “clear” when compared with thiopental. Propofol is not considered an analgesic, so opioids such as fentanyl may be combined with propofol to alleviate pain.

Propofol has been referred to as milk of amnesia (a play on words of milk of magnesia), because of the milk-like appearance of its intravenous preparation.

It is on the World Health Organization’s List of Essential Medicines, the most important medications needed in a health system.


Level II: propofol may control ICP after several hours of dosing, but it does not improve mortality or 6-month outcomes. ✖ Caution: high-dose propofol (total dose > 100 mg/kg for > 48 hrs) can cause significant morbidity (see propofol infusion syndrome).

℞: 0.5 mg/kg test dose, then 20–75 mcg/kg/min infusion. Increase by 5–10 mcg/kg/min q 5–10 minutes PRN ICP control (do not exceed 83 mcg/kg/min = 5 mg/kg/hr).

Side effects include propofol infusion syndrome. Use with caution at doses > 5 mg/kg/hr or at any dose for > 48 hrs.


Propofol, an established hypnotic anesthetic agent, has been shown to ameliorate neuronal injury when given after injury in a number of experimental brain studies. We tested the hypothesis that propofol pretreatment confers neuroprotection against SBI and will reduce cerebral edema formation and neurobehavioral deficits in our rat population. Sprague-Dawley rats were treated with low- and high-dose propofol 30 min before SBI. At 24 h post-injury, brain water content and neurobehavioral assessment was conducted based on previously established models. In vehicle-treated rats, SBI resulted in significant cerebral edema and higher neurological deficit scores compared with sham-operated rats. Low- or high-dose propofol therapy neither reduced cerebral edema nor improved neurologic function. The results suggest that propofol pretreatment fails to provide neuroprotection in SBI rats. However, it is possible that an SBI model with less magnitude of injury or that propofol re-dosing, given the short-acting pharmacokinetic property of propofol, may be needed to provide definitive conclusions 2).


Propofol concentration needed for induction of unconsciousness in 50% of patients is reduced in Parkinson’s Disease patients 3).

Malekmohammadi et al. from the Department of Neurosurgery, University of California, Los Angeles, collected local field potentials (LFPs) in 12 awake and anesthetized PD patients undergoing DBS implantation. Spectral power of β (13-35 Hz) and high-frequency oscillations (HFOs: 200-300 Hz) was compared across the pallidum.

Propofol suppressed GPi power by > 20 Hz while increasing power at lower frequencies. A similar power shift was observed in GPe; however, power in the high β range (20-35 Hz) increased with propofol. Before anesthesia both β and HFO activity were significantly greater at the GPi (χ2 = 20.63 and χ2 = 48.81, p < 0.0001). However, during anesthesia, we found no significant difference across the pallidum (χ2 = 0.47, p = 0.79, and χ2 = 4.11, p = 0.12).

GPi and GPe are distinguishable using LFP spectral profiles in the awake condition. Propofol obliterates this spectral differentiation. Therefore, LFP spectra cannot be relied upon in the propofol-anesthetized state for functional mapping during DBS implantation 4).


We analyzed 231 neurosurgery patients. In all patients, propofol was used for standard anesthesia induction. Patient demographics, medical histories, fasting duration, percentage weight loss, baseline blood pressure, and PPV during normal tidal volume breathing and that during forced inspiratory breathing (PPVfi) were recorded. Hemodynamic changes within 10 minutes of intubation were observed. Patients developing hypotension and severe hypotension were determined; lowest mean arterial pressure (MAP) and systolic arterial pressure (SAP) values were recorded, and their differences relative to baseline values were calculated. RESULTS: The incidence of hypotension was 18.6%. Both percentage weight loss and PPVfi were correlated with the changes in MAP and SAP. A PPVfi>14 identified all observed hypotensive episodes with 86% sensitivity and 86.2% specificity, whereas percentage weight loss >1.75% identified all observed hypotensive episodes with 81.4% sensitivity and 70.7% specificity. Furthermore, PPVfi>16.5 identified severe hypotension with 85% sensitivity and 90.5% specificity, whereas percentage weight loss >1.95% identified severe hypotension with 85% sensitivity and 73% specificity. CONCLUSIONS: Percentage weight loss and PPVfi are good predictors of hypotension after anesthesia induction and, thus, may allow anesthesiologists to adopt preventative measures and ensure safer anesthesia induction 5).

Acute psychosis following propofol in a patient with Parkinson’s disease: effects of a GABAdopamine imbalance 6).

What is the primary use of Propofol in clinical practice? a) Pain relief b) Induction and maintenance of general anesthesia c) Treatment of hypertension d) Treatment of epilepsy

What is the advantage of using Propofol for induction of anesthesia? a) It provides prolonged anesthesia. b) It has a slow onset of action. c) It causes rapid loss of consciousness. d) It is available in oral form.

How does Propofol compare to some other anesthetic agents in terms of its duration of action? a) It has a longer duration of action. b) It has a shorter duration of action. c) It has no duration of action. d) Its duration of action depends on the patient’s age.

What state does Propofol induce in patients during surgery? a) Euphoria b) Sedation and amnesia c) Hyperactivity d) Increased pain perception

How is Propofol administered during surgery? a) Orally b) Intramuscularly c) Subcutaneously d) As a controlled IV infusion

What is one of the common side effects of Propofol during surgery? a) Increased heart rate b) Hypertension (high blood pressure) c) Respiratory depression d) Elevated body temperature

What property of Propofol makes it useful in preventing postoperative nausea and vomiting? a) Analgesic effect b) Antidepressant effect c) Antiemetic properties d) Anticoagulant effect

What rare condition can occur with prolonged and high-dose use of Propofol? a) Hypothermia b) Propofol overdose c) Propofol-related infusion syndrome (PRIS) d) Propofol addiction

Which of the following statements about Propofol is true? a) It is commonly used as a standalone analgesic. b) It is available in various forms, including oral tablets. c) It is administered exclusively through IV injection. d) It is primarily used as an anticoagulant.

Why is Propofol known as the “milk of amnesia”? a) It has a white color. b) It is derived from milk. c) It tastes like milk. d) It causes amnesia-like effects.

Answers:

b) Induction and maintenance of general anesthesia c) It causes rapid loss of consciousness. b) It has a shorter duration of action. b) Sedation and amnesia d) As a controlled IV infusion c) Respiratory depression c) Antiemetic properties c) Propofol-related infusion syndrome (PRIS) c) It is administered exclusively through IV injection. a) It has a white color.


1)

Liu EH, Wong HK, Chia CP, et al. Effects of isoflurane and propofol on cortical somatosensory evoked potentials during comparable depth of anaesthesia as guided by bispectral index. Br J Anaesth. 2005; 94:193–197
2)

Pakkianathan C, Benggon M, Khatibi NH, Chen H, Marcantonio S, Applegate R 2nd, Tang J, Zhang J. Propofol Pretreatment Fails to Provide Neuroprotection Following a Surgically Induced Brain Injury Rat Model. Acta Neurochir Suppl. 2016;121:323-7. doi: 10.1007/978-3-319-18497-5_56. PubMed PMID: 26463969.
3)

Xu XP, Yu XY, Wu X, Hu XW, Chen JC, Li JB, Wang JF, Deng XM. Propofol Requirement for Induction of Unconsciousness Is Reduced in Patients with Parkinson’s Disease: A Case Control Study. Biomed Res Int. 2015;2015:953729. Epub 2015 Oct 1. PubMed PMID: 26495319.
4)

Malekmohammadi M, Sparks H, AuYong N, Hudson A, Pouratian N. Propofol Anesthesia Precludes LFP-Based Functional Mapping of Pallidum during DBS Implantation. Stereotact Funct Neurosurg. 2018 Sep 7:1-10. doi: 10.1159/000492231. [Epub ahead of print] PubMed PMID: 30196280.
5)

Ali A, Altiparmak O, Tetik A, Altun D, Sivrikoz N, Buget M, Bolsoy S, Yaman N, Akinci IO. Pulse Pressure Variation and Weight-Loss Percentage Predict Hypotension After Anesthesia Induction in Neurosurgery Patients: A Prospective, Observational, Blinded Study. J Neurosurg Anesthesiol. 2016 Jun 17. [Epub ahead of print] PubMed PMID: 27322092.
6)

Vinckier F, Gaillard R, Taylor G, Murray GK, Plaze M, Bourdillon P, Perin-Dureau F. Acute psychosis following propofol in a patient with Parkinson’s disease: effects of a GABA-dopamine imbalance. Psychiatry Clin Neurosci. 2022 Mar 29. doi: 10.1111/pcn.13360. Epub ahead of print. PMID: 35352434.

DECSA trial

DECSA trial

Chronic subdural hematoma (CSDH) is a common neurological disease with a rapidly rising incidence due to increasing age and widespread use of anticoagulants. Surgical intervention by burr hole craniotomy (BHC) is the current standard practice for symptomatic patients, but associated with complications, a chronic subdural hematoma recurrence rate of up to 30% and increased mortalityDexamethasone (DXM) therapy is, therefore, used as a non-surgical alternative but considered to achieve a lower success rate. Furthermore, the benefit of DXM therapy appears much more deliberate than the immediate relief from BHC. Lack of evidence and clinical equipoise among caregivers prompts the need for a head-to-head randomised controlled trial. The objective of this study is to compare the effect of primary DXM therapy versus primary BHC on functional outcome and cost-effectiveness in symptomatic patients with CSDH.


In a multicenteropen-labelcontrollednoninferiority trial, Miah et al. randomly assigned symptomatic patients with chronic subdural hematoma in a 1:1 ratio to a 19-day tapering course of dexamethasone or to burr-hole drainage. The primary endpoint was the functional outcome at 3 months after randomization, as assessed by the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Noninferiority was defined by a lower limit of the 95% confidence interval of the odds ratio for a better functional outcome with dexamethasone than with surgery of 0.9 or more. Secondary endpoints included scores on the Markwalder Grading Scale of symptom severity and on the Extended Glasgow Outcome Scale.

From September 2016 through February 2021, we enrolled 252 patients of a planned sample size of 420; 127 were assigned to the dexamethasone group and 125 to the surgery group. The mean age of the patients was 74 years, and 77% were men. The trial was terminated early by the data and safety monitoring board owing to safety and outcome concerns in the dexamethasone group. The adjusted common odds ratio for a lower (better) score on the modified Rankin scale at 3 months with dexamethasone than with surgery was 0.55 (95% confidence interval, 0.34 to 0.90), which failed to show noninferiority of dexamethasone. The scores on the Markwalder Grading Scale and Extended Glasgow Outcome Scale were generally supportive of the results of the primary analysis. Complications occurred in 59% of the patients in the dexamethasone group and 32% of those in the surgery group, and additional surgery was performed in 55% and 6%, respectively.

In a trial that involved patients with a chronic subdural hematoma and that was stopped early, dexamethasone treatment was not found to be non-inferior to burr-hole drainage with respect to functional outcomes and was associated with more complications and a greater likelihood of later surgery. (Funded by the Netherlands Organization for Health Research and Development and others; DECSA EudraCT number, 2015-001563-39.) 1).


Consecutive patients with a CSDH with a Markwalder Grading Scale (MGS) grade 1 to 3 were randomized to treatment with DXM or BHC. The DXM treatment scheme was 16 mg DXM per day (8 mg twice daily, days 1 to 4) which is then halved every 3 days until a dosage of 0.5 mg a day on day 19 and stopped on day 20. If the treatment response is insufficient (i.e. persistent or progressive symptomatology due to insufficient hematoma resolution), additional surgery can be performed. The primary outcomes are the functional outcome by means of the modified Rankin Scale (mRS) score at 3 months and cost-effectiveness at 12 months. Secondary outcomes are quality of life at 3 and 12 months using the Short Form Health Survey (SF-36) and Quality of Life after Brain Injury Overall Scale (QOLIBRI), hematoma thickness after 2 weeks on follow-up computed tomography (CT), hematoma recurrence during the first 12 months, complications and drug-related adverse events, failure of therapy within 12 months after randomization and requiring intervention, mortality during the first 3 and 12 months, duration of hospital stay and overall healthcare and productivity costs. To test the non-inferiority of DXM therapy compared to BHC, 210 patients in each treatment arm are required (assumed adjusted common odds ratio DXM compared to BHC 1.15, the limit for inferiority < 0.9). The aim was to include a total of 420 patients in 3 years with an enrolment rate of 60%.

The present study should demonstrate whether treatment with DXM is as effective as BHC on functional outcomes, at lower costs.

TRIAL REGISTRATION:

EUCTR 2015-001563-39 . Date of registration: 29 March 2015 2)


1)

Miah IP, Holl DC, Blaauw J, Lingsma HF, den Hertog HM, Jacobs B, Kruyt ND, van der Naalt J, Polinder S, Groen RJM, Kho KH, van Kooten F, Dirven CMF, Peul WC, Jellema K, Dammers R, van der Gaag NA; DECSA Collaborators. Dexamethasone versus Surgery for Chronic Subdural Hematoma. N Engl J Med. 2023 Jun 15;388(24):2230-2240. doi: 10.1056/NEJMoa2216767. PMID: 37314705.
2)

Miah IP, Holl DC, Peul WC, Walchenbach R, Kruyt N, de Laat K, Koot RW, Volovici V, Dirven CMF, van Kooten F, Kho KH, den Hertog HM, van der Naalt J, Jacobs B, Groen RJM, Lingsma HF, Dammers R, Jellema K, van der Gaag NA; Dutch Subdural Hematoma Research Group (DSHR). Dexamethasone therapy versus surgery for chronic subdural haematoma (DECSA trial): study protocol for a randomised controlled trial. Trials. 2018 Oct 20;19(1):575. doi: 10.1186/s13063-018-2945-4. PubMed PMID: 30342554.

Peptic ulcer disease

Peptic ulcer disease

Steroid side effects

In 1932Harvey Cushing described peptic ulceration secondary to raised intracranial pressure and attributed this to vagal overactivity, causing excess gastric acid secretion. Cushing ulcer remains a cause of morbidity in patients, albeit one that is preventable.

Kumaria et al. evaluate the evidence pertaining to the pathophysiology of neurogenic peptic ulceration. A literature review suggests that the pathophysiology of Cushing ulcer may extend beyond vagal mechanisms for several reasons: (1) clinical and experimental studies have shown only a modest increase in gastric acid secretion in head injury patients; (2) increased vagal tone is found in only a minority of cases of intracranial hypertension, most of which are related to catastrophic, nonsurvivable brain injury; (3) direct stimulation of the vagus nerve does not cause peptic ulceration, and; (4) Cushing ulcer can occur after acute ischemic stroke, but only a minority of strokes are associated with raised intracranial pressure and/or increased vagal tone. The 2005 Nobel Prize in Medicine honored the discovery that bacteria play key roles in the pathogenesis of peptic ulcer disease. Brain injury results in widespread changes in the gut microbiome in addition to gastrointestinal inflammation, including systemic upregulation of proinflammatory cytokines. Alterations in the gut microbiome in patients with severe traumatic brain injury include colonization with commensal flora associated with peptic ulceration. The brain-gut-microbiome axis integrates the central nervous system, the enteric nervous system, and the immune system.

They propose a novel hypothesis that neurogenic peptic ulcer may be associated with alterations in the gut microbiome, resulting in gastrointestinal inflammation leading to ulceration 1).

Omeprazole for Adults with peptic ulcers or gastroesophageal reflux disease (GERD) 20–40 mg PO daily. For Zollinger-Ellison syndrome: 20 mg PO q d to 120 mg PO TID (dose adjusted to keep basal acid output < 60 mEq/hr).

Side effects: N/V, H/A, diarrhea, abdominal pain, or rash in 1–5% of patients. Supplied: 10, 20 & 40 mg delayed-release capsules. Available OTC in 20.6 mg tablets as Prilosec OTC.


Misoprostol (Cytotec®), a prostaglandin, may be effective in mitigating NSAID-induced gastric erosion or peptic ulcer. Contraindicated in pregnancy. ℞ 200 mcg PO QID with food as long as the patient is on NSAIDs. If not tolerated, use 100 mcg. ✖ CAUTION: an abortifacient. Should not be given to pregnant women or women of childbearing potential


1)

Kumaria A, Kirkman MA, Scott RA, Dow GR, Leggate AJ, Macarthur DC, Ingale HA, Smith SJ, Basu S. A Reappraisal of the Pathophysiology of Cushing Ulcer: A Narrative Review. J Neurosurg Anesthesiol. 2023 May 11. doi: 10.1097/ANA.0000000000000918. Epub ahead of print. PMID: 37188653.

Regorafenib side effects

Regorafenib side effects

 


Some of the most common side effects of regorafenib include:

Fatigue

Diarrhea

Nausea and vomiting

Loss of appetite

Hand-foot syndrome (redness, swelling, and pain on the palms of the hands and soles of the feet)

High blood pressure

Abdominal pain

Headache

Weight loss

Infections


Extensive coagulative necrosis 1).


One patient experienced, after reintervention and during Regorafenib treatment (administered 40 days after surgery), dehiscence of the surgical wound 2)


In patients with progressive WHO grade 3 or 4 gliomas, predominantly with two pretreatment lines or more, regorafenib seems to be effective despite considerable grade 3 or 4 side effects 3).


Treiber et al. described 11 consecutive patients with high-grade glioma recurrence treated with regorafenib at the university medical center in Göttingen. The majority of patients had MGMT promoter methylation (9/11 cases). Regorafenib was given as 2nd line systemic treatment in 6/11 patients and 3rd or higher line treatment in 5/11 patients. The median number of applied cycles was 2 with dosage reductions on 5/11. Response to treatment was observed on 4/11 (PR on 1/11, and SD on 3/11). The Median overall survival for the cohort was 16.1 months, median progression-free survival was 9.0 months, and median time to treatment failure was 3.3 months. Side effects of any CTCAE grade were noted in all patients, hereby 6/11 with CTCAE °III-IV reactions. High-grade side effects were of dermatologic, cardiovascular, and hematologic nature. A mean treatment delay of 57.5 days (range 23-119) was noted between tumor board recommendation and treatment initiation due to the application process for off-label use in this indication. In conclusion, treatment with regorafenib in relapsed high-grade glioma is a feasible treatment option but has to be considered carefully due to the significant side effect profile 4).


Within 12-months of regorafenib treatment, and 16-years since SRS, the patient developed ipsilateral House-Brackmann Grade IV facial weakness. Dramatic VS expansion from 14 to 25 mm in maximum diameter, with new brain stem compression, was seen on MRI. Due to poor prognosis of his gastrointestinal malignancy, he declined surgical resection, and elected for palliative salvage SRS 5).


1) 
Werner JM, Wollring MM, Tscherpel C, Rosen EK, Werr L, Stetter I, Rueß D, Ruge MI, Brunn A, Al Shughri A, Kabbasch C, Fink GR, Langen KJ, Galldiks N. Multimodal imaging findings in patients with glioblastoma with extensive coagulative necrosis related to regorafenib. Neuro Oncol. 2023 Mar 24:noad051. doi: 10.1093/neuonc/noad051. Epub ahead of print. PMID: 36960770.
2) 
Gregucci F, Surgo A, Carbonara R, Laera L, Ciliberti MP, Gentile MA, Caliandro M, Sasso N, Bonaparte I, Fanelli V, Tortora R, Paulicelli E, Surico G, Lombardi G, Signorelli F, Fiorentino A. Radiosurgery and Stereotactic Brain Radiotherapy with Systemic Therapy in Recurrent High-Grade Gliomas: Is It Feasible? Therapeutic Strategies in Recurrent High-Grade Gliomas. J Pers Med. 2022 Aug 20;12(8):1336. doi: 10.3390/jpm12081336. PMID: 36013284; PMCID: PMC9410141.
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Werner JM, Wolf L, Tscherpel C, Bauer EK, Wollring M, Ceccon G, Deckert M, Brunn A, Pappesch R, Goldbrunner R, Fink GR, Galldiks N. Efficacy and tolerability of regorafenib in pretreated patients with progressive CNS grade 3 or 4 gliomas. J Neurooncol. 2022 Jun 18. doi: 10.1007/s11060-022-04066-9. Epub ahead of print. PMID: 35716310.
4) 
Treiber H, von der Brelie C, Malinova V, Mielke D, Rohde V, Chapuy CI. Regorafenib for recurrent high-grade glioma: a unicentric retrospective analysis of feasibility, efficacy, and toxicity. Neurosurg Rev. 2022 Jun 20. doi: 10.1007/s10143-022-01826-z. Epub ahead of print. PMID: 35725846.
5) 
Carlstrom LP, Muñoz-Casabella A, Perry A, Graffeo CS, Link MJ. Dramatic Growth of a Vestibular Schwannoma After 16 Years of Postradiosurgery Stability in Association With Exposure to Tyrosine Kinase Inhibitors. Otol Neurotol. 2021 Dec 1;42(10):e1609-e1613. doi: 10.1097/MAO.0000000000003304. PMID: 34766951; PMCID: PMC8597893.

Condoliase for lumbar disc herniation

Condoliase for lumbar disc herniation


Percutaneous chemonucleolysis with condoliase has been available for painful lumbar disc herniation since 2018 in Japan.


In the 1980s, chemonucleolysis with chymopapain, a protease, was widely used as the intermediate treatment between conservative therapy and surgical therapy in Western countries. However, since chymopapain was withdrawn from the market in 2002 for non-scientific commercial reasons, chemonucleolysis has not been a therapeutic option for LDH. Condoliase (chondroitin sulfate ABC endolyase), a glycosaminoglycan-degrading enzyme, was approved by the drug regulatory authority in Japan as a newer intradiscal therapy for LDH after clinical studies conducted in Japan demonstrated efficacy and safety for patients with LDH 1)


Condoliase as a first-line treatment option ahead of surgical treatment for LDH is superior, from a cost perspective to surgical treatment from the beginning. Condoliase is also a cost-effective alternative to non-surgery conservative treatment 2).

Patients between 20 and 70 years of age with unilateral leg pain, positive findings on the straight leg raise test, and LDH were recruited. All eligible patients were randomly assigned to receive condoliase (1.25, 2.5, or 5 U) or placebo. The primary end point was a change in the worst leg pain from preadministration (baseline) to week 13. The secondary end points were changes from baseline in the following items: worst back pain, Oswestry Disability Index (ODI), SF-36, and neurological examination. For pharmacokinetic and pharmacodynamic analyses, plasma condoliase concentrations and serum keratan sulfate concentrations were measured. The safety end points were adverse events (AEs) and radiographic and MRI parameters. Data on leg pain, back pain, abnormal neurological findings, and imaging parameters were collected until week 52. RESULTS A total of 194 patients received an injection of condoliase or placebo. The mean change in worst leg pain from baseline to week 13 was -31.7 mm (placebo), -46.7 mm (1.25 U), -41.1 mm (2.5 U), and -47.6 mm (5 U). The differences were significant at week 13 in the 1.25-U group (-14.9 mm; 95% CI -28.4 to -1.4 mm; p = 0.03) and 5-U group (-15.9 mm; 95% CI -29.0 to -2.7 mm; p = 0.01) compared with the placebo group. The dose-response improvement in the worst leg pain at week 13 was not significant (p = 0.14). The decrease in the worst leg pain in all 3 condoliase groups was observed from week 1 through week 52. Regarding the other end points, the worst back pain and results of the straight leg raise test, ODI, and SF-36 showed a tendency for sustained improvement in each of the condoliase groups until week 52. In all patients at all time points, plasma condoliase concentrations were below the detectable limit (< 100 μU/ml). Serum keratan sulfate concentrations significantly increased from baseline to 6 hours and 6 weeks after administration in all 3 condoliase groups. No patient died or developed anaphylaxis or neurological sequelae. Five serious AEs occurred in 5 patients (3 patients in the condoliase groups and 2 patients in the placebo group), resolved, and were considered unrelated to the investigational drug. Severe AEs occurred in 10 patients in the condoliase groups and resolved or improved. In the condoliase groups, back pain was the most frequent AE. Modic type 1 change and decrease in disc height were frequent imaging findings. Dose-response relationships were observed for the incidence of adverse drug reactions and decrease in disc height. CONCLUSIONS Condoliase significantly improved clinical symptoms in patients with LDH and was well tolerated. While all 3 doses had similar efficacy, the incidence of adverse drug reactions and decrease in disc height were dose dependent, thereby suggesting that 1.25 U would be the recommended clinical dose of condoliase. Clinical trial registration no.: NCT00634946 (clinicaltrials.gov) 3).

Ohtonari et al. investigated clinical and radiographic outcomes three months after the administration because secondary surgical removal is most required during this period for insufficient pain relief, and analyzed whether the differences in intradiscal injection areas affected the clinical outcomes. They retrospectively investigated 47 consecutive patients (males, 31; median age, 40 years) three months after the administration. Clinical outcomes were evaluated using the Japanese Orthopaedic Association Back Pain Questionnaire (JOABPEQ), a visual analog scale (VAS) score for low back pain, and VAS scores for pains and numbness in the lower limbs. Radiographic outcomes were analyzed in 41 patients, using parameters such as mid-sagittal disc height and maximal protrusion length of herniation on MRI preoperatively and at the final follow-up. The postoperative median evaluation period was 90 days. The effective rate of low back pain based on the pain-related disorders at baseline and the last follow-up in the JOABPEQ reached 79.5%. The postoperative proportion of VAS scores recovery ≥ 2 points and ≥ 50% for pains in the lower limbs were 80.9% and 66.0%, respectively, revealing satisfactory effectiveness. Preoperative median mid-sagittal disc height significantly reduced from 9.5 to 7.6 mm postoperatively. There were no significant differences in pain relief in the lower limbs by injection areas in the center and the dorsal 1/3rd near the herniation of the nucleus pulposus. Chemonucleolysis with condoliase revealed satisfactory short-term outcomes after the administration regardless of intradiscal injection areas 4).


101 patients who underwent chemonucleolysis with condoliase from January 2019 to December 2021. Patients were divided into good outcome (i.e., favorable outcome) and poor outcome (i.e., requiring additional surgical treatment) groups. Patient demographics and imaging findings were collected. Clinical outcomes were evaluated using the numerical rating scale and Japanese Orthopaedic Association scores at baseline and at 1- and 3-month follow-up. Pretreatment indicators for additional surgery were compared between the 2 groups. Results: There was a significant difference in baseline leg numbness between the good outcome and poor outcome groups (6.27 ± 1.90 vs. 4.42 ± 2.90, respectively; p = 0.033). Of the 101 included patients, 32 received a preoperative computed tomography scan. In those patients, the presence of calcification or ossification in disc hernia occurred more often in the poor outcome group (61.5% vs. 5.3%, respectively; p &lt; 0.001; odds ratio = 22.242; p = 0.014). Receiver-operating characteristics curve analysis for accompanying calcification or ossification showed an area under the curve of 0.858 (95% confidence interval, 0.715-1.000; p = 0.001). Conclusions: Calcified or ossified disc herniation may be useful predictors of unsuccessful treatment in patients with condoliase administration 5).


Sixty-seven patients (44 men, 23 women; mean age, 46.7 ± 18.0 years) were analyzed. Time-course changes in disc height, disc degeneration, and herniation size were assessed. For clinical outcomes assessment, visual analog scale (VAS) scores for leg and back pain and the Oswestry disability index (ODI) were obtained at baseline and the 3-month, 1-year, and 2-year follow-ups. We obtained a questionnaire from these patients at two years to assess satisfaction and recommendation. Condoliase therapy was considered to be effective in patients whose VAS score for leg pain improved by ≥ 50% at 2 years from baseline and who did not require surgery.

Results: Condoliase therapy was effective in 51 patients (76.1%). Eight patients (11.9%) required surgery due to ineffectiveness of the therapy. Condoliase therapy was ineffective in five out of six patients with a history of discectomy. The ODI and VAS scores for leg and back pain significantly improved from three months to two years. Of the patients, 80% satisfied with their outcomes, and 85% recommended this therapy. Progression of disc degeneration was observed in 57.1% of patients at three months; however, 30% recovered to baseline at two years. The mean disc height decreased at three months, but recovered slightly at one year and remained stable until two years. No recurrent disc herniation was observed.

Conclusions: Chemonucleolysis with condoliase was effective in 78% of patients with LDH for 2 years. Chemonucleolysis-induced disc degeneration was slightly recovered and maintained for two years post-injection. This treatment resulted in high patient satisfaction and recommendations 6).


137 LDH patients treated through condoliase at four Japanese institutions and assessed its effectiveness among different age categories on alleviation of visual analog scale (VAS) of leg pain, low back pain and numbness, as well as ODI and JOA scores. Moreover, we divided them into either a “group-A” category if a ≥50% improvement in baseline leg pain VAS was observed or “group-N” if VAS leg pain improved &lt;50%. Next, we assessed the differences in clinical and demographic distribution between group-A and group-N. Results: Fifty-five patients were classified as group-A (77.5%) and 16 patients were allocated to group-N (22.5%). A significant difference in Pfirrmann classification was found between both cohorts, with grade IV suggested to be most receptive. A posterior disc angle &gt; 5° was also found to approach statical significance. In all age groups, average VAS scores showed improvement. However, 75% of adolescent patients showed deterioration in Pfirrmann classification following treatment. Conclusions: Intradiscal condoliase injection is an effective treatment for LDH, even in patients with large vertebral translation and posterior disc angles, regardless of age. However, since condoliase imposes a risk of progressing disc degeneration, its indication for younger patients remains controversial 7).


Medical records and radiographic findings were reviewed retrospectively for 127 patients with LDH (88 male, 39 female, mean age: 46.6 ± 17.1 years, mean follow-up: 9.8 ± 7.8 months) who underwent chemonucleolysis with intradiscal condoliase injection at our center since September 2018. Condoliase (1.25 U/mL; 1 mL volume) was injected toward the middle of the affected intervertebral nucleus pulposus using a 21-gauge disc-puncture needle.

Results: Cases in which the Pfirrmann grade did and did not progress in the 3 months after the injection were included in groups P (progression, n = 49) and NP (non-progression, n = 78), respectively. Logistic regression analysis of progression of Pfirrmann grade post-injection showed significant associations with age <40 years (p = 0.013, odds ratio (OR): 3.69, 95% confidence interval (CI): 1.32-10.31), Pfirrmann Grade II or III at baseline (p = 0.021, OR: 3.51, 95% CI: 1.24-9.64), and a high-intensity MRI signal in the herniation (p = 0.047, OR: 2.97, 95% CI: 1.03-8.87). Patients in group P had significantly higher rates of disc height decrease ≥20%, reduced herniated disc size, and improved VAS for pain, but both groups had significant decreases in pain. No cases had an anaphylactic shock or neurologic sequelae.

Conclusions: These results show the safety and efficacy of chemonucleolysis with condoliase for treatment of painful LDH. Progression of Pfirrmann criteria on MRI at 3 months after injection was significantly associated with an improved clinical outcome 8).


Seventy patients (85.4%) were classified into the effective (E) group and 12 patients (14.6%) into the less-effective (L) group. Surgical treatment was required in four patients. No severe adverse complications were reported; 41.3% of the patients developed disc degeneration of Pfirrmann grade 1 or more at the injected disc level. Univariate analysis revealed that young age (p = 0.036), without history of epidural or nerve root block (p = 0.024), and injection into the central portion of the intervertebral disc (p = 0.014) were significantly associated with clinical effectiveness. A logistic regression analysis revealed that injection into the central portion of the intervertebral disc (p = 0.049; odds ratio, 4.913; 95% confidence interval, 1.006-26.204) was significantly associated with clinical effectiveness.

Conclusions: Chemonucleolysis with condoliase is a safe and effective treatment for painful LDH; 85.4% of the patients showed improvement after the treatment without severe adverse events. To obtain the best outcome, condoliase should be injected into the center of the intervertebral disc 9).


Forty-seven patients (20 women, 27 men; mean age 48 years) were included. The herniation level was L2/3 in one patient, L3/4 in two, L4/5 in 23, and L5/S1 in 21. Median symptom duration was 8 months. The mean VAS and ODI improved significantly from the baseline to 3-month follow-up (p < 0.01). Group E included 33 patients (70.2%) and group I included 14, three of whom had a history of discectomy. The rates of spondylolisthesis and posterior intervertebral angle ≥5° were significantly higher in group I than in group E. However, the rates of trans-ligamentous type and herniation with high signal intensity on T2-weighted images (highT2) were significantly higher in group E. Reduction of disc herniation was more frequently observed in group E.

Conclusions: Condoliase injection resulted in significantly improved symptoms in patients with LDH. Condoliase therapy was less effective for patients with a history of discectomy, spondylolisthesis, or those with a posterior intervertebral angle ≥5°, while trans-ligamentous type and high T2 herniation were associated with increased efficacy 10)


A total of 52 patients (mean age, 45.0 years) were enrolled and classified according to whether the injection was effective (E group, n=40, 76.9%) or less effective (L group, n=9, 17.3%). Three patients (5.8%) underwent herniotomy for residual pain within 6 months of the injection. There were no severe adverse events. Reduction of herniation was seen on MRI more often in the E group than in the L group. The effectiveness in patients with transligamentous LDH was similar to that in patients with subligamentous LDH. High-intensity signal change in the area of LDH on pretreatment T2-weighted MRI was a significant predictor of successful leg pain relief.

Conclusions: An intradiscal condoliase injection was a safe and effective treatment for painful radiculopathy caused by LDH. Leg pain was more likely to improve in patients with high-intensity signal change in the area of LDH before treatment 11).


In total, 84 patients were recruited (52 men, 32 women; mean age, 44.2 ± 17.1 [16-86 years]). The duration of illness was 6.7 ± 6.8 (1.5-30) months. All patient-based outcomes significantly improved at 4 weeks after the administration compared with pretreatment. The intervertebral disc height decreased significantly at four weeks after condoliase administration compared with that before administration. Progression of intervertebral disc degeneration occurred in 50% of the patients. Eleven patients underwent herniotomy due to poor treatment effects. Moreover, treatment in 77.4% of the patients was considered effective. A logistic regression analysis revealed that L5/S1 disk administration (p = 0.029; odds ratio, 5.94; 95% confidence interval, 1.20-29.45) were significantly associated with clinical effectiveness.

Conclusions: Condoliase disk administration improved pain and quality of life over time. Condoliase disk administration was more effective in L5/S1 intervertebral administration 12).


47 patients who received condoliase, 34 were enrolled in this study. The mean age of the patients was 33 years. The average duration since the onset of disease was 8.6 months. We evaluated patients’ low back and leg pain using a numerical rating scale (NRS) score at two time points (before therapy and 3 months after therapy). We divided the patients into two groups (good group (G): NRS score improvement ≥ 50%, poor group (P): NRS score improvement < 50%). The parameters evaluated were age, disease duration, body mass index (BMI), and positive or negative straight leg raising test results. In addition, the loss of disc height and preoperative radiological findings were evaluated. Results: In terms of low back and leg pain, the G group included 9/34 (26.5%) and 21/34 (61.8%) patients, respectively. Patients’ age (low back pain G/P, 21/36.5 years) was significantly lower in the G group for low back pain (p = 0.001). High-intensity change in the protruded nucleus pulposus (NP) and spinal canal occupancy by the NP ≥ 40% were significantly high in those with leg pain in the G groups (14/21, p = 0.04; and 13/21, p = 0.03, respectively). Conclusions: The efficacy of improvement in leg pain was significantly correlated with high-intensity change and size of the protruded NP. Condoliase was not significantly effective for low back pain but could have an effect on younger patients 13).


42 patients with LDH who underwent intradiscal condoliase injection. Patients with and without a ≥50% improvement from baseline of leg pain at 3 months after injection were defined as responders and non-responders, respectively. Clinical features and radiological findings were compared between these groups.

Results: Of the 42 patients, 32 (76.2%) were responders and 10 (23.8%) were non-responders. Of 8 patients with a history of discectomy at the same level as LDH, 6 (75.0%) were responders. Non-responders had a significantly longer time from onset to treatment, smaller herniated volume before treatment, lower percentage reduction of herniated mass, and less intervertebral disc degeneration before treatment. There were no significant differences in LDH types (subligamentous extrusion or transligamentous extrusion types), high-intensity area within the herniation, changes in disc height, and region of condoliase injection between the two groups.

Conclusions: Intradiscal condoliase injection had a good short-term therapeutic effect in patients with LDH, including in transligamentous extrusion-type and revision cases as well as subligamentous extrusion-type cases. Administration of intradiscal condoliase injection may be most effective in patients with a larger herniated mass volume before treatment, and least effective in cases with a longer time and less intervertebral disc degeneration before treatment 14).


A total of 82 and 81 patients received an injection of condoliase and placebo, respectively. The average changes in worst leg pain from baseline to week 13 (primary endpoint) were -49.5 mm in the condoliase group and -34.3 mm in the placebo group, and the difference of -15.2 mm was significant (95% confidence interval, -24.2 to -6.2; P = 0.001). Significant improvements were observed in the condoliase groups, compared with the placebo group, in most secondary endpoints at 1 year after administration. In the condoliase group, back pain, Modic type 1 change, and decrease in disc height were frequently reported, without any clinically relevant consequences.

Conclusion: Condoliase significantly improved symptoms in patients with LDH and was well tolerated. Condoliase is a novel and potent chemonucleolytic drug for the treatment of LDH 15).

It has been available for painful lumbar disc herniation since 2018 in Japan.

A 25-year-old man with a history of LDH in L4/5, who underwent transforaminal full endoscopic lumbar discectomy when he was 17 years old, complained of severe pain radiating to his left leg for 1 month. The straight leg-raising test was limited to 25° on the left side. Lumbar T2-weighted magnetic resonance imaging (MRI) showed intracanal, left-sided transligamentous disc herniation at L4/5 with high-signal intensity. Because the conservative treatment with oral analgesics and selective left L5 nerve root block failed, the patient requested intradiscal condoliase injection instead of revision surgery. There were no adverse events reported after the condoliase treatment, and the pain radiating to the left leg improved within 2 weeks. A lumbar MRI performed 2 months after treatment revealed that the disc herniation had significantly decreased in size. The straight leg-raising test examined 3 months after treatment was negative. In this case, the disc herniation was of the transligamentous type and showed a high-signal intensity on T2-weighted MRI which could be suitably treated by condoliase injection therapy. This case report is the first to suggest that intradiscal condoliase injection could be a useful and novel conservative treatment option to treat postoperative rec-LDH 16).


1)

Matsuyama Y, Chiba K. Condoliase for treatment of lumbar disc herniation. Drugs Today (Barc). 2019 Jan;55(1):17-23. doi: 10.1358/dot.2019.55.1.2899445. PMID: 30740609.
2)

Takaki S, Miyama H, Iwasaki M. Cost-effectiveness analysis of intradiscal condoliase injection vs. surgical or conservative treatment for lumbar disc herniation. J Med Econ. 2023 Jan-Dec;26(1):233-242. doi: 10.1080/13696998.2023.2173465. PMID: 36794375.
3)

Matsuyama Y, Chiba K, Iwata H, Seo T, Toyama Y. A multicenter, randomized, double-blind, dose-finding study of condoliase in patients with lumbar disc herniation. J Neurosurg Spine. 2018 May;28(5):499-511. doi: 10.3171/2017.7.SPINE161327. Epub 2018 Feb 9. PMID: 29424676.
4)

Ohtonari T, Torii R, Noguchi S, Kitagawa T, Nishihara N. Short-term clinical and radiographic outcomes of chemonucleolysis with condoliase for painful lumbar disc herniation and analysis regarding intradiscal injection area. Neurosurg Rev. 2023 Feb 23;46(1):59. doi: 10.1007/s10143-023-01966-w. PMID: 36813932.
5)

Takeuchi S, Hanakita J, Takahashi T, Inoue T, Minami M, Suda I, Nakamura S, Kanematsu R. Predictive Factors for Poor Outcome following Chemonucleolysis with Condoliase in Lumbar Disc Herniation. Medicina (Kaunas). 2022 Dec 18;58(12):1868. doi: 10.3390/medicina58121868. PMID: 36557070; PMCID: PMC9781337.
6)

Banno T, Hasegawa T, Yamato Y, Yoshida G, Arima H, Oe S, Ide K, Yamada T, Kurosu K, Nakai K, Matsuyama Y. Condoliase therapy for lumbar disc herniation -2 year clinical outcome. J Orthop Sci. 2022 Nov 21:S0949-2658(22)00317-7. doi: 10.1016/j.jos.2022.11.005. Epub ahead of print. PMID: 36424250.
7)

Oshita Y, Matsuyama D, Sakai D, Schol J, Shirasawa E, Emori H, Segami K, Takahashi S, Yagura K, Miyagi M, Saito W, Imura T, Nakazawa T, Inoue G, Hiyama A, Katoh H, Akazawa T, Kanzaki K, Sato M, Takaso M, Watanabe M. Multicenter Retrospective Analysis of Intradiscal Condoliase Injection Therapy for Lumbar Disc Herniation. Medicina (Kaunas). 2022 Sep 15;58(9):1284. doi: 10.3390/medicina58091284. PMID: 36143959; PMCID: PMC9501482.
8)

Kobayashi K, Sato K, Ando T. Factors associated with disc degeneration based on Pfirrmann criteria after condoliase treatment for lumbar disc herniation. J Orthop Sci. 2022 Aug 24:S0949-2658(22)00230-5. doi: 10.1016/j.jos.2022.08.001. Epub ahead of print. PMID: 36030156.
9)

Okada E, Suzuki S, Nori S, Tsuji O, Nagoshi N, Yagi M, Fujita N, Nakamura M, Matsumoto M, Watanabe K. The effectiveness of chemonucleolysis with condoliase for treatment of painful lumbar disc herniation. J Orthop Sci. 2021 Jul;26(4):548-554. doi: 10.1016/j.jos.2020.06.004. Epub 2020 Jul 23. PMID: 32713796.
10)

Banno T, Hasegawa T, Yamato Y, Yoshida G, Yasuda T, Arima H, Oe S, Ushirozako H, Yamada T, Ide K, Watanabe Y, Matsuyama Y. Clinical outcome of condoliase injection treatment for lumbar disc herniation: Indications for condoliase therapy. J Orthop Sci. 2021 Jan;26(1):79-85. doi: 10.1016/j.jos.2020.02.002. Epub 2020 Feb 25. PMID: 32111547.
11)

Hirai T, Takahashi T, Tanaka T, Motoyoshi T, Matsukura Y, Yuasa M, Inose H, Yoshii T, Okawa A. Intradiscal Injection with Condoliase (Chondroitin Sulfate ABC Endolyase) for Painful Radiculopathy Caused by Lumbar Disc Herniation. Spine Surg Relat Res. 2021 Oct 11;6(3):252-260. doi: 10.22603/ssrr.2021-0151. PMID: 35800623; PMCID: PMC9200423.
12)

Inoue M, Sainoh T, Kojima A, Yamagata M, Morinaga T, Mannoji C, Ataka H, Yamashita M, Takahashi H, Saito J, Fujiyoshi T, Ishikawa T, Eguchi Y, Kato K, Orita S, Inage K, Shiga Y, Norimoto M, Umimura T, Shiko Y, Kawasaki Y, Aoki Y, Ohtori S. Efficacy and Safety of Condoliase Disc Administration as a New Treatment for Lumbar Disc Herniation. Spine Surg Relat Res. 2021 Jun 11;6(1):31-37. doi: 10.22603/ssrr.2021-0035. PMID: 35224244; PMCID: PMC8842352.
13)

Ishibashi K, Fujita M, Takano Y, Iwai H, Inanami H, Koga H. Chemonucleolysis with Chondroitin Sulfate ABC Endolyase for Treating Lumbar Disc Herniation: Exploration of Prognostic Factors for Good or Poor Clinical Outcomes. Medicina (Kaunas). 2020 Nov 19;56(11):627. doi: 10.3390/medicina56110627. PMID: 33228119; PMCID: PMC7699387.
14)

Nakajima H, Kubota A, Maezawa Y, Watanabe S, Honjoh K, Ohmori H, Matsumine A. Short-Term Outcome and Predictors of Therapeutic Effects of Intradiscal Condoliase Injection for Patients with Lumbar Disc Herniation. Spine Surg Relat Res. 2020 Nov 20;5(4):264-271. doi: 10.22603/ssrr.2020-0126. PMID: 34435150; PMCID: PMC8356240.
15)

Chiba K, Matsuyama Y, Seo T, Toyama Y. Condoliase for the Treatment of Lumbar Disc Herniation: A Randomized Controlled Trial. Spine (Phila Pa 1976). 2018 Aug 1;43(15):E869-E876. doi: 10.1097/BRS.0000000000002528. PMID: 29257028.
16)

Funayama T, Setojima Y, Shibao Y, Noguchi H, Miura K, Eto F, Sato K, Kono M, Asada T, Takahashi H, Tatsumura M, Koda M, Yamazaki M. A Case of Postoperative Recurrent Lumbar Disc Herniation Conservatively Treated with Novel Intradiscal Condoliase Injection. Case Rep Orthop. 2022 Feb 15;2022:3656753. doi: 10.1155/2022/3656753. PMID: 35211348; PMCID: PMC8863464.

Delirium Diagnosis

Delirium Diagnosis


Unlike dementiadelirium has an acute onset, motor signs (tremormyoclonusasterixis), slurred speech, altered consciousness (hyperalert/agitated or lethargic, or fluctuations), hallucinations may be florid.

Consultation-liaison psychiatry could improve the recognition rate of postoperative delirium in elderly patients, and shorten hospitalization time. The training of mental health knowledge for non-psychiatrists could improve the ability of early identify and treatment of delirium 1).


It is a corollary of the criteria that a diagnosis of delirium usually cannot be made without a previous assessment, or knowledge, of the affected person’s baseline level of cognitive function. In other words, a mentally disabled person who is suffering from this will be operating at their own baseline level of mental ability and would be expected to appear delirious without a baseline mental functional status against which to compare.

Early detection is crucial because the longer a patient experiences delirium the worse it becomes and the harder it is to treat. Currently, identification is through intermittent clinical assessment using standardized tools, like the Confusion Assessment Method for the Intensive Care Unit. Such tools work well in clinical research but do not translate well into clinical practice because they are subjective, intermittent, and have low sensitivity. As such, healthcare providers using these tools fail to recognize delirium symptoms as much as 80% of the time.

EEG shows pronounced diffuse slowing.

Delirium-related biochemical derangement leads to electrical changes in electroencephalographic (EEG) patterns followed by behavioral signs and symptoms. However, continuous EEG monitoring is not feasible due to the cost and the need for skilled interpretation. Studies using limited-lead EEG show large differences between patients with and without delirium while discriminating delirium from other causes. The Ceribell is a limited-lead device that analyzes EEG. If it is capable of detecting delirium, it would provide an objective physiological monitor to identify delirium before symptom onset. This pilot study was designed to explore relationships between Ceribell and delirium status. Completion of this study will provide a foundation for further research regarding delirium status using the Ceribell data 2).


Hut SC, Dijkstra-Kersten SM, Numan T, Henriquez NR, Teunissen NW, van den Boogaard M, Leijten FS, Slooter AJ. EEG and clinical assessment in delirium and acute encephalopathy. Psychiatry Clin Neurosci. 2021 May 16. doi: 10.1111/pcn.13225. Epub ahead of print. PMID: 33993579.


Early neutrophil-to-lymphocyte ratio (NLR) elevation may also predict delayed-onset delirium, potentially implicating systemic inflammation as a contributory delirium mechanism 3).

Older age, headache, coagulopathy, decreased level of consciousness, seizures, and history of falls. Conversely, infection was associated with a reduced yield.

In higher-risk patients and settings, there should be a push toward earlier neuroimaging as indicated by clinical examinations and individual risk factors. In the meta-analysis, the yield of head CT was higher in ICU patients and those who had focal neurological deficits in addition to altered mental status and was especially high in neuro ICU settings 4)

Neuroimaging should not replace a clinical exam, even in ICU settings; ICU patients should have their sedation reduced to properly test for delirium 5).

Delirium has a complex and fluctuating course with underlying causes that are often multifactorial; identifying a CNS lesion does not necessarily exclude other causes, and vice-versa 6).

The risks of neuroimaging need to be considered in the decision-making process 7).

The use of CT head to diagnose the etiology of delirium and AMS varied widely and yield has declined. Guidelines and clinical decision support tools could increase the appropriate use of CT head in the diagnostic etiology of delirium/AMS 8).


1)

Xie Q, Liu XB, Jing GW, Jiang X, Liu H, Zhong BL, Li Y. The Effect of Consultation-Liaison Psychiatry on Postoperative Delirium in Elderly Hip Fracture Patients in the General Hospital. Orthop Surg. 2023 Jan 3. doi: 10.1111/os.13501. Epub ahead of print. PMID: 36597675.
2)

Mulkey MA, Hardin SR, Munro CL, Everhart DE, Kim S, Schoemann AM, Olson DM. Methods of identifying delirium: A research protocol. Res Nurs Health. 2019 May 30. doi: 10.1002/nur.21953. [Epub ahead of print] PubMed PMID: 31148216.
3)

Reznik ME, Kalagara R, Moody S, Drake J, Margolis SA, Cizginer S, Mahta A, Rao SS, Stretz C, Wendell LC, Thompson BB, Asaad WF, Furie KL, Jones RN, Daiello LA. Common biomarkers of physiologic stress and associations with delirium in patients with intracerebral hemorrhage. J Crit Care. 2021 Mar 23;64:62-67. doi: 10.1016/j.jcrc.2021.03.009. Epub ahead of print. PMID: 33794468.
4)

MadsenTE, KhouryJ, Cadena R, et al. Potentially missed diagnosis of ischemic stroke in the Emergency Department in the Greater Cincinnati/Northern Kentucky stroke study.Acad Emerg Med. 2016;23(10):1128-1135. doi:10.1111/acem.13029
5)

Venkat A, Cappelen-Smith C, Askar S, et al. Factors associated with stroke misdiagnosis in the emergency department: a retrospective case-control study. Neuroepidemiology. 2018;51(3–4):123-127. doi:10.1159/000491635
6)

The 2019 American Geriatrics Society Beers Criteria®UpdateExpert Panel. American Geriatrics Society 2019 updated AGSbeers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019;67(4):674-694. doi:10.1111/jgs.15767
7)

Reznik ME, Rudolph JL. “Yield” to the time-brain dilemma: The case for neuroimaging in delirium. J Am Geriatr Soc. 2023 Jan 6. doi: 10.1111/jgs.18206. Epub ahead of print. PMID: 36606371.
8)

Akhtar H, Chaudhry SH, Bortolussi-Courval É, Hanula R, Akhtar A, Nauche B, McDonald EG. Diagnostic yield of CT head in delirium and altered mental status-A systematic review and meta-analysis. J Am Geriatr Soc. 2022 Nov 26. doi: 10.1111/jgs.18134. Epub ahead of print. PMID: 36434820.

Linezolid in Neurosurgery

Linezolid in Neurosurgery

Relevant studies were identified through searches of the PubMed, Current Contents, and Cochrane databases (publications archived until October 2006).

Case reports, case series, prospective and retrospective studies, and randomized controlled trials were eligible for inclusion in our review if they evaluated the effectiveness and safety of linezolid for the treatment of patients with CNS infections.

In 18 (42.9%) of the 42 relevant cases identified, patients had undergone neurosurgical operations and/or had prosthetic devices. Meningitis was the most common CNS infection, accounting for 20 (47.6%) cases. Other CNS infections included brain abscesses (14; 33.3%), ventriculitis (5; 11.9%), and ventriculo-peritoneal shunt infection (3; 7.1%). In the 39 patients in whom the responsible pathogen was isolated, those predominantly responsible for the CNS infections were: penicillin-nonsusceptible Streptococcus pneumoniae (7; 17.9%), vancomycin-resistant enterococci (6; 15.4%), Nocardia spp. (5; 12.8%), methicillin-resistant Staphylococcus epidermidis (4; 10.3%), and methicillin-resistant Staphylococcus aureus (3; 7.7%). Of the 42 patients who received linezolid for the treatment of CNS infections, 38 (90.5%) were either cured or showed clinical improvement of the infection. The mean duration of follow-up was 7.2 months; no recurrent CNS infection was reported.

The limited published data suggest that linezolid may be considered for the treatment of patients with CNS infections in cases of failure of previously administered treatment or limited available options 2).

To evaluate the efficacy and safety of SAT with oral linezolid in patients with NSI and to analyse the cost implications, an observational, non-comparative, prospective cohort study was conducted on clinically stable consecutive adult patients at the Neurosurgical Service. Following intravenous treatment, patients were discharged with SAT with oral linezolid.

A total of 77 patients were included. The most common NSIs were: 41 surgical wound infections, 20 subdural empyemas, 18 epidural abscesses, and 16 brain abscesses. Forty-four percent of patients presented two or more concomitant NSIs. Aetiological agents commonly isolated were: Propionibacterium acnes (36 %), Staphylococcus aureus (23 %), Staphylococcus epidermidis (21 %) and Streptococcus spp. (13 %). The median duration of the SAT was 15 days (range, 3-42). The SAT was interrupted in five cases due to adverse events. The remainder of the patients were cured at the end of the SAT. A total of 1,163 days of hospitalisation were saved. An overall cost reduction of €516,188 was attributed to the SAT. Eight patients with device infections did not require removal of the device, with an additional cost reduction of €190,595. The mean cost saving per patient was €9,179.

SAT with linezolid was safe and effective for the treatment of NSI. SAT reduces hospitalisation times, which means significant savings of health and economic resources 3).


Seventeen patients were included in the study. The main comorbidities among these patients included one or more of the following: subarachnoidal or intraventricular hemorrhage (n=8), solid neurological cancer (n=7), corticosteroids(n=9), and hydrocephalus (n=6). Eight patients underwent a craniotomy and fourteen patients had external ventricular drainage (EVD) as a predisposing factor for infection. Meningitis was the most common infection (11; 64.7%), followed by ventriculitis (4; 23.5%) and brain abscesses (2;11.8%). The main causative organisms were coagulase-negative Staphylococcus spp. (13; 76.5%). Linezolid was used as the initial therapy in 8 episodes, after therapy failure in 6, and for other reasons in 3. The oral route was used in 9 (52.9%) episodes; linezolid was initiated orally in 2 cases. The mean duration of treatment was 26.5 days (range 15-58). No adverse events were reported. Sixteen (94.1%) patients were considered cured. There was one recurrence. The mean length of hospital stay was 45.6 (range 15-112) days and the mean duration of follow-up was 7.2 (range 0.4-32) months. No related deaths occurred during active episodes.

Linezolid was mainly indicated in post-neurosurgical EVD-associated infections due to coagulase-negative Staphylococcus spp. It was used as initial therapy in most cases. A high rate of clinical cure was observed and no related adverse events were reported. More than half of the patients benefited from the advantages of the oral route of administration 4).


In order to study the penetration of this antimicrobial into the cerebrospinal fluid (CSF) of such patients, the disposition of linezolid in serum and CSF was studied in 14 neurosurgical patients given linezolid at 600 mg twice daily (1-h intravenous infusion) for the treatment of CNS infections caused by gram-positive pathogens or for prophylactic chemotherapy. Serum and CSF linezolid steady-state concentrations were analyzed by high-pressure liquid chromatography, and the concentration-time profiles obtained were analyzed to estimate pharmacokinetic parameters. The mean +/- standard deviation (SD) linezolid maximum and minimum measured concentrations were 18.6 +/- 9.6 microg/ml and 5.6 +/- 5.0 microg/ml, respectively, in serum and 10.8 +/- 5.7 microg/ml and 6.1 +/- 4.2 microg/ml, respectively, in CSF. The mean +/- SD areas under the concentration-time curves (AUCs) were 128.7 +/- 83.9 microg x h/ml for serum and 101.6 +/- 59.6 microg x h/ml for CSF, with a mean penetration ratio for the AUC for CSF to the AUC for serum of 0.66. The mean elimination half-life of linezolid in CSF was longer than that in serum (19.1 +/- 19.0 h and 6.5 +/- 3.6 h, respectively). The serum and CSF linezolid concentrations exceeded the pharmacodynamic breakpoint of 4 microg/ml for susceptible target pathogens for the entire dosing interval in the majority of patients. These findings suggest that linezolid may achieve adequate concentrations in the CSF of patients requiring antibiotics for the management or prophylaxis of CNS infections caused by gram-positive pathogens 5).


1)

Jahoda D, Nyc O, Pokorný D, Landor I, Sosna A. [Linezolid in the treatment of antibiotic-resistant gram-positive infections of the musculoskeletal system]. Acta Chir Orthop Traumatol Cech. 2006 Oct;73(5):329-33. Czech. PubMed PMID: 17140514.
2)

Ntziora F, Falagas ME. Linezolid for the treatment of patients with central nervous system infection. Ann Pharmacother. 2007 Feb;41(2):296-308. Epub 2007 Feb 6. Review. PubMed PMID: 17284501.
3)

Martín-Gandul C, Mayorga-Buiza MJ, Castillo-Ojeda E, Gómez-Gómez MJ, Rivero-Garvía M, Gil-Navarro MV, Márquez-Rivas FJ, Jiménez-Mejías ME. Sequential antimicrobial treatment with linezolid for neurosurgical infections: efficacy, safety and cost study. Acta Neurochir (Wien). 2016 Oct;158(10):1837-43. doi: 10.1007/s00701-016-2915-0. Epub 2016 Aug 13. PubMed PMID: 27520361.
4)

Sousa D, Llinares P, Meijide H, Gutiérrez JM, Miguez E, Sánchez E, Castelo L, Mena A. Clinical experience with linezolid for the treatment of neurosurgical infections. Rev Esp Quimioter. 2011 Mar;24(1):42-7. PMID: 21412669.
5)

Myrianthefs P, Markantonis SL, Vlachos K, Anagnostaki M, Boutzouka E, Panidis D, Baltopoulos G. Serum and cerebrospinal fluid concentrations of linezolid in neurosurgical patients. Antimicrob Agents Chemother. 2006 Dec;50(12):3971-6. doi: 10.1128/AAC.00051-06. Epub 2006 Sep 18. PMID: 16982782; PMCID: PMC1694012.

Somatostatin analogs in meningioma

Somatostatin analogs in meningioma

Meningiomas are associated with several sex hormones-related risk factors and demonstrate a predominance in females. These associations led to investigations of the role that hormones may have on meningioma growth and development. While it is now accepted that most meningiomas express progesterone and somatostatin receptors, the conclusion for other receptors has been less definitive.

Miyagishima et al. performed a review of what is known regarding the relationship between hormones and meningiomas in the published literature. Furthermore, they reviewed clinical trials related to hormonal agents in meningiomas using MEDLINE PubMedScopus, and the NIH clinical trials database.

They identified that all steroid-hormone trials lacked receptor identification or positive receptor status in the majority of patients. In contrast, four out of five studies involving somatostatin analogs used positive receptor status as part of the inclusion criteria.

Several clinical trials have recently been completed or are now underway using somatostatin analogs in combination with other therapies that appear promising, but a reevaluation of hormone-based monotherapy is warranted. Synthesizing this evidence, they clarified the remaining questions and present future directions for the study of the biological role and therapeutic potential of hormones in meningioma and discuss how the stratification of patients using features such as grade, receptor status, and somatic mutations, might be used for future trials to select patients most likely to benefit from specific therapies 1)


Jensen et al. performed an individual patient data (IPD) meta-analysis. Main outcomes were toxicity, best radiological response, progression-free survival, and overall survival. They applied multivariable logistic regression models to estimate the effect of SSA on the probability of obtaining radiological disease control. The predictive performance was evaluated using area under the curve and Brier scores. They included 16 studies and compiled IPD from 8/9 of all previous cohorts. Quality of evidence was overall ranked “very low.” Stable disease was reported in 58% of patients as best radiological response. Per 100 mg increase in total SSA dosage, the odds ratios for obtaining radiological disease control was 1.42 (1.11 to 1.81, P = 0.005) and 1.44 (1.00 to 2.08, P = 0.05) for patients treated with SSA as monodrug therapy vs SSA in combination with everolimus, respectively. Low quality of evidence impeded exact quantification of treatment efficacy, and the association between response and treatment may represent reverse causality. Yet, the SSA treatment was well tolerated, and beneficial effect cannot be disqualified. A prospective trial without bias from inconsistency in study designs is warranted to assess somatostatin analog therapy for well-defined meningioma subgroups 2).

Between January 1996 and December 2010, 13 patients harboring a progressive residual meningioma (as indicated by MR imaging criteria) following operative therapy were treated with a monthly injection of the SST analog octreotide (Sandostatin LAR [long-acting repeatable] 30 mg, Novartis). Eight of 13 patients had a meningioma of the skull base and were analyzed in the present study. Postoperative tumor enlargement was documented in all patients on MR images obtained before the initiation of SST therapy. All tumors were benign. No patient received radiation or chemotherapy before treatment with SST. The growth of residual tumor was monitored by MR imaging every 12 months.

Results: Three of the 8 patients had undergone surgical treatment once; 3, 2 times; and 2, 3 times. The mean time after the last meningioma operation (before starting SST treatment) and tumor enlargement as indicated by MR imaging criteria was 24 months. A total of 643 monthly cycles of Sandostatin LAR were administered. Five of the 8 patients were on SST continuously and stabilized disease was documented on MR images obtained in these patients during treatment (median 115 months, range 48-180 months). Three of the 8 patients interrupted treatment: after 60 months in 1 case because of tumor progression, after 36 months in 1 case because of side effects, and after 36 months in 1 case because the health insurance company denied cost absorption.

Conclusions: Although no case of tumor regression was detected on MR imaging, the study results indicated that SST analogs can arrest the progression of unresectable or recurrent benign meningiomas of the skull base in some patients. It remains to be determined whether a controlled prospective clinical trial would be useful 3).


1)

Miyagishima DF, Moliterno J, Claus E, Günel M. Hormone therapies in meningioma-where are we? J Neurooncol. 2022 Nov 23. doi: 10.1007/s11060-022-04187-1. Epub ahead of print. PMID: 36418843.
2)

Jensen LR, Maier AD, Lomstein A, Graillon T, Hrachova M, Bota D, Ruiz-Patiño A, Arrieta O, Cardona AF, Rudà R, Furtner J, Roeckle U, Clement P, Preusser M, Scheie D, Broholm H, Kristensen BW, Skjøth-Rasmussen J, Ziebell M, Munch TN, Fugleholm K, Walter MA, Mathiesen T, Mirian C. Somatostatin analogues in treatment-refractory meningioma: a systematic review with meta-analysis of individual patient data. Neurosurg Rev. 2022 Oct;45(5):3067-3081. doi: 10.1007/s10143-022-01849-6. Epub 2022 Aug 19. PMID: 35984552.
3)

Schulz C, Mathieu R, Kunz U, Mauer UM. Treatment of unresectable skull base meningiomas with somatostatin analogs. Neurosurg Focus. 2011 May;30(5):E11. doi: 10.3171/2011.1.FOCUS111. PMID: 21529167.

Glioblastoma recurrence treatment

Glioblastoma recurrence treatment

There is no consensus as to the standard of care as no therapeutic options have produced substantial survival benefit for Glioblastoma recurrences (Glioblastomas) 1) 2).

A purely radiological diagnosis of recurrence or progression can be hampered by flaws induced by pseudoprogressionpseudoresponse, or radionecrosis

There is sufficient uncertainty and equipoise regarding the question of reoperation for patients with Glioblastoma recurrence to support the need for a randomized controlled trial 3).


Based on parameters like localization and tumor volume, patient’s Karnofsky Performance Score, time from initial diagnosis, and availability of alternative salvage therapies, reoperation can be considered as a treatment option to extend the overall survival and quality of life of the patient.

The achieved extent of resection of the relapsed tumor—especially with the intention of having a safe, complete resection of the enhancing tumor—most likely plays a crucial role in the ultimate outcome and prognosis of the patient, regardless of other modes of treatment. Validated scores to predict the prognosis after reoperation of a patient with a Glioblastoma recurrence can help to select suitable candidates for surgery. Safety issues and complication avoidance are pivotal to maximally preserving the patient’s quality of life. Besides a possible direct oncological effect, resampling of the recurrent tumor with detailed pathological and molecular analysis might have an impact on the development, testing, and validation of new salvage therapies 4).

Options include repeat surgical resection, repeat fractionated radiation, radiosurgery.

Bevacizumab (BEV) plus daily temozolomide (TMZ) as a salvage therapy has been recommended for recurrent glioma.


In a study, Hundsberger et al investigated which treatments are currently being used for recurrent Glioblastoma within a single nation (Switzerland) and how clinicians are deciding to use them 5)

The authors surveyed Swiss hospitals with comprehensive multidisciplinary neuro-oncology practices (neurosurgery, radiation therapy, medical neuro-oncology, and a dedicated neuro-oncology tumor board) about treatment recommendations for recurrent Glioblastoma. They identified relevant clinical decision-making criteria, called diagnostic nodes or “dodes,” and compared treatment recommendations using a decision-tree format.

Eight hospitals participated. The most common treatment options for recurrent Glioblastoma were combination repeat surgical resection with temozolomide or bevacizumab, monotherapy temozolomide or bevacizumab, and best supportive care. Alternative therapies, including radiotherapy, were less common. Despite widespread disagreement between centers in clinical decision-making, the decision-tree analysis found agreement (>63%) between most centers for only 4 specific clinical scenarios. Patients without an appropriate performance status were usually managed with the best supportive care. Patients with rapid recurrence, nonresectable tumors, unmethylated O(6)-methylguanine DNA methyltransferase (MGMT) promoter, and high-performance status were usually managed with bevacizumab. Patients with late recurrence, nonresectable tumors, overt clinical symptoms, methylated MGMT promoter, multifocal disease, and high-performance status were usually managed with repeat temozolomide therapy. Patients with late recurrence, nonresectable tumors, no clinical symptoms, methylated MGMT promoter, tumor multifocality, and high-performance status were usually managed with temozolomide. The findings of this study underscore the lack of effective first- and second-line treatments for Glioblastoma, and the interhospital variability in practice patterns is not surprising. It seems likely that similar heterogeneity would also be noted in a study of American neuro-oncology centers. It is interesting to note that despite the availability of an increasing number of molecular markers for Glioblastoma stratification, MGMT promoter methylation appears to be the only biological marker widely used across multiple centers in this study. It remains to be seen when and how broadly other markers such as the epidermal growth factor receptor variant III or isocitrate dehydrogenase mutations will be adopted for clinical decision-making. The authors are to be congratulated for identifying core clinical decision-making criteria that may be useful in future studies of recurrent Glioblastoma. This decision tree is an excellent reference for clinical trial development, and several active clinical trials already target the dudes identified in this study. Subsequent studies may help to determine whether similar decision trees exist in American neuro-oncologic centers now or will exist in the future 6).

Figure. A through F, clinical decision-making tree for Glioblastoma recurrence multiforme (Glioblastoma) based on clinical scenarios that achieved a majority recommendation (ie, at least 5 of 8 Swiss hospitals). BEV, bevacizumab; BSC, best supportive care; rGlioblastoma, Glioblastoma recurrence multiforme; TMZ, temozolomide. Modified with kind permission from Springer Science+Business Media: Journal of Neuro-Oncology, Patterns of care in Glioblastoma recurrence in Switzerland: a multicenter national approach based on diagnostic nodes (published online ahead of print October 12. 2015), Hundsberger T, Hottinger AF, Roelcke U, et al [doi: 10.1007/s11060-015-1957-0. Available at: http://link.springer.com/article/10.1007%2Fs11060-015-1957-0 ].

Temozolomide rechallenge is a treatment option for MGMT promoter-methylated Glioblastoma recurrence. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation 7).

Intrarterial chemotherapy is a viable methodology in recurrent Glioblastoma patients to prolong survival at the risk of procedure-related complications and in newly diagnosed patients with the benefit of decreased complications 8).

Low-dose fractionated radiotherapy LD-FRT and chemotherapy for recurrent/progressive Glioblastoma have a good toxicity profile and clinical outcomes, even though further investigation of this novel palliative treatment approach is warranted 9).

Second surgery plus carmustine wafers followed by intravenous fotemustine in twenty-four patients were analyzed. The median age was 53.6; all patients had KPS between 90 and 100; 19 patients (79%) performed a gross total resection > 98% and 5 (21%) a gross total resection > 90%. The median progression-free survival from second surgery was 6 months (95% CI 3.9-8.05) and the median OS was 14 months (95% CI 11.1-16.8 months). Toxicity was predominantly haematological: 5 patients (21%) experienced grade 3-4 thrombocytopenia and 3 patients (12%) grade 3-4 leukopenia.

This multimodal strategy may be feasible in patients with Glioblastoma recurrence, in particular, for patients in good clinical conditions 10).

The HSPPC-96 vaccine is safe and warrants further study of efficacy for the treatment of recurrent Glioblastoma. Significant pretreatment lymphopenia may impact the outcomes of immunotherapy and deserves additional investigation 11).

see Laser interstitial thermotherapy.

Galldiks et al monitored the metabolic effects of stereotaxy-guided LITT in a patient with a recurrent Glioblastoma using amino acid positron emission tomography (PET). Serial 11C-methyl-L-methionine positron emission tomography (MET-PET) and contrast-enhanced computed tomography (CT) were performed using a hybrid PET/CT system in a patient with recurrent Glioblastoma before and after LITT. To monitor the biologic activity of the effects of stereotaxy-guided LITT, a threshold-based volume of interest analysis of the metabolically active tumor volume (MET uptake index of ≥ 1.3) was performed. A continuous decline in metabolically active tumor volume after LITT could be observed. MET-PET seems to be useful for monitoring the short-term therapeutic effects of LITT, especially when patients have been pretreated with a multistep therapeutic regimen. MET-PET seems to be an appropriate tool to monitor and guide experimental LITT regimens and should be studied in a larger patient group to confirm its clinical value 12).

Adjuvant lomustine to other chemotherapy may provide no obvious benefits for the glioblastoma recurrence treatment 13).

A more favorable prognosis following surgery for recurrence or progression is associated with younger age, smaller tumor volume (~50%), motor speech-middle cerebral artery scoring and preoperative Karnofsky performance score (KPS) >80% 14) 15).

Optimal treatment for recurrent High-grade glioma continues to evolve. Currently, however, there is no consensus in the literature on the role of reoperation in the management of these patients.

An analysis, of reoperation in patients with World Health Organization grade III or IV recurrent gliomas, focusing on how reoperation affects outcome, perioperative complications, and quality of life. An extensive literature review was performed through the use of the PubMed and Ovid Medline databases for January 1980 through August 2013. A total 31 studies were included in the final analysis. Of the 31 studies with significant data from single or multiple institutions, 29 demonstrated a survival benefit or improved functional status after reoperation for recurrent high-grade glioma. Indications for reoperation included new focal neurological deficits, tumor mass effect, signs of elevated intracranial pressure, headaches, increased seizure frequency, and radiographic evidence of tumor progression. Age was not a contraindication to reoperation. Time interval of at least 6 months between operations and favorable performance status (Karnofsky Performance Status score ≥70) were important predictors of benefit from reoperation. Extent of resection at reoperation improved survival, even in patients with subtotal resection at initial operation. Careful patient selection such as avoiding those individuals with poor performance status and bevacizumab within 4 weeks of surgery is important. Although limited to retrospective analysis and patient selection bias, mounting evidence suggests a survival benefit in patients receiving a reoperation at the time of high-grade glioma recurrence 16).

Twenty patients with recurrent glioma were treated with BEV (5-10 mg/kg, i.v. every 2 weeks) plus daily TMZ (daily, 50 mg/m2). The treatment response was evaluated via the RANO criteria. HRQL were measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (QLQ-C30) and Brain Module (QLQ-BN20).

Twenty patients received a total of 85 cycles of BEV with a median number of 4 cycles (range: 2-10). No patients showed complete response (CR) to treatment. Twelve patients had partial response (PR), stable disease (SD) in 5 patients with, and 3 patients showed progressive disease (PD). In the functioning domains of QLQ-C30, physical functioning, cognitive functioning and emotional functioning significantly improved after the second cycle of BEV compared to baseline, with the mean score of 45.0 vs. 64.0 (p = 0.020), 55.8 vs. 71.7 (p = 0.020) and 48.3 vs. 67.5 (p = 0.015), respectively. In the symptom scales, the scores of pain and nausea/vomiting significantly decreased compared to baseline from the mean score of 39.1 to 20.0 (p = 0.020) and 29.2 to 16.7 (p = 0.049), respectively. Score of global health status also increased from 47.5 to 63.3 (p = 0.001). As determined with the QLQ-BN20, motor dysfunction (43.3 vs. 25.0, p = 0.021), weakness of legs (36.7 vs. 18.3, p = 0.049), headache (38.3 vs. 20.0, p = 0.040), and drowsiness (50.0 vs. 30.0, p = 0.026) after the second cycle of BEV also significantly improved compared to baseline.

BEV plus daily TMZ as a salvage therapy improved HRQL in patients with recurrent glioma 17).

Quick-Weller et al. performed tumour resections in seven patients with rGlioblastoma, combining 5-ALA (20 mg/kg bodyweight) with iMRI (0.15 T). Radiologically complete resections were intended in all seven patients.

They assessed intraoperative fluorescence findings and compared these with intraoperative imaging. All patients had early postoperative MRI (3 T) to verify final iMRI scans and received adjuvant treatment according to interdisciplinary tumour board decision.

Median patient age was 63 years. Median KPS score was 90, and median tumour volume was 8.2 cm(3). In six of seven patients (85%), 5-ALA induced fluorescence of tumour-tissue was detected intraoperatively. All tumours were good to visualise with iMRI and contrast media. One patient received additional resection of residual contrast enhancing tissue on intraoperative imaging, which did not show fluorescence. Radiologically complete resections according to early postoperative MRI were achieved in all patients. Median survival since second surgery was 7.6 months and overall survival since diagnosis was 27.8 months.

5-ALA and iMRI are important surgical tools to maximise tumour resection also in rGlioblastoma. However, not all rGlioblastomas exhibit fluorescence after 5-ALA administration. They propose the combined use of 5-ALA and iMRI in the surgery of rGlioblastoma 18).

In some case series reoperation extends survival by an additional 36 weeks in patients with glioblastoma, and 88 weeks in anaplastic astrocytoma 19) 20) (duration of high-quality survival was 10 weeks and 83 weeks, respectively, and was lower with pre-op Karnofsky score < 70). In addition to Karnofsky performance score, significant prognosticators for response to repeat surgery include: age and time from the first operation to reoperation (shorter times → worse prognosis) 21). Morbidity is higher with reoperation (5–18%); the infection rate is ≈ 3x that for first operation, wound dehiscence is more likely


1)

Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treatment of Glioblastoma recurrence–are we there yet? Neuro Oncol. 2013 Jan;15(1):4-27. doi: 10.1093/neuonc/nos273. Epub 2012 Nov 7. Review. PubMed PMID: 23136223; PubMed Central PMCID: PMC3534423.
2)

Lukas RV, Mrugala MM (2017) Pivotal trials for infiltrating gliomas and how they affect clinical practice. Neuro Oncol Pract 4:209–219
3)

Patel M, Au K, Davis FG, Easaw JC, Mehta V, Broad R, Chow MMC, Hockley A, Kaderali Z, Magro E, Nataraj A, Scholtes F, Chagnon M, Gevry G, Raymond J, Darsaut TE. Clinical Uncertainty and Equipoise in the Management of Glioblastoma recurrence. Am J Clin Oncol. 2021 Mar 29. doi: 10.1097/COC.0000000000000812. Epub ahead of print. PMID: 33782334.
4)

Dejaegher J, De Vleeschouwer S. Recurring Glioblastoma: A Case for Reoperation? In: De Vleeschouwer S, editor. Glioblastoma [Internet]. Brisbane (AU): Codon Publications; 2017 Sep 27. Chapter 14. Available from http://www.ncbi.nlm.nih.gov/books/NBK469991/ PubMed PMID: 29251867.
5)

Hundsberger T, Hottinger AF, Roelcke U, et al.. Patterns of care in Glioblastoma recurrence in Switzerland: a multicentre national approach based on diagnostic nodes [published online ahead of print October 12, 2015]. J Neuro Oncol. doi: 10.1007/s11060-015-1957-0. Available at: http://link.springer.com/article/10.1007%2Fs11060-015-1957-0.
6)

Zussman BM, Engh JA. Patterns of Care and Clinical Decision Making for Glioblastoma recurrence Multiforme. Neurosurgery. 2016 Feb;78(2):N12-4. doi: 10.1227/01.neu.0000479889.72124.20. PubMed PMID: 26779791.
7)

Weller M, Tabatabai G, Kästner B, Felsberg J, Steinbach JP, Wick A, Schnell O, Hau P, Herrlinger U, Sabel MC, Wirsching HG, Ketter R, Bähr O, Platten M, Tonn JC, Schlegel U, Marosi C, Goldbrunner R, Stupp R, Homicsko K, Pichler J, Nikkhah G, Meixensberger J, Vajkoczy P, Kollias S, Hüsing J, Reifenberger G, Wick W; DIRECTOR Study Group. MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial. Clin Cancer Res. 2015 May 1;21(9):2057-64. doi: 10.1158/1078-0432.CCR-14-2737. Epub 2015 Feb 5. PubMed PMID: 25655102.
8)

Theodotou C, Shah AH, Hayes S, Bregy A, Johnson JN, Aziz-Sultan MA, Komotar RJ. The role of intra-arterial chemotherapy as an adjuvant treatment for glioblastoma. Br J Neurosurg. 2014 Jan 16. [Epub ahead of print] PubMed PMID: 24432794.
9)

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