Management

Thiopental

Thiopental

Thiopental (Pentothal®)

Thiopental in neurosurgery

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

Protocol

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).

Test and Answers

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.

References

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.

Antibiotics for spondylodiscitis treatment

Antibiotics for spondylodiscitis treatment

Antibiotic therapy is a pillar of treatment for spondylodiscitis and should be a part of the treatment in all cases. Neurologic deficits, sepsis, intraspinal empyema, the failure of conservative treatment, and spinal instability are all indications for surgical treatment 1).

Randomized trials to guide the selection of the appropriate route, duration, or agent for antibiotic therapy are lacking. Practice is based on retrospective case series, expert opinion, and data extrapolated from animal and laboratory data.

Choice

The choice of antibiotics for the treatment of spondylodiscitis depends on several factors, including the suspected or identified causative microorganism, the severity of the infection, and individual patient factors such as allergies and underlying medical conditions. Empirical antibiotic therapy may be initiated before the exact microorganism is identified based on clinical presentation and risk factors. However, once the causative organism is identified through cultures, antibiotic therapy can be adjusted accordingly. Commonly implicated bacteria in pyogenic spondylodiscitis include Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus or MRSA), Streptococcus species, and Escherichia coli.

Here are some antibiotic options commonly used for the treatment of spondylodiscitis:

Empirical Antibiotics: These antibiotics may be started before the specific microorganism is identified. Common choices include:

Intravenous (IV) antibiotics such as ceftriaxone or cefotaxime plus MRSA coverage with vancomycin or daptomycin. Broad-spectrum antibiotics like piperacillin-tazobactam or meropenem in critically ill patients with risk factors for multidrug-resistant organisms. Specific Antibiotics: Once the causative organism is identified, the antibiotics can be tailored to target that particular microorganism. Antibiotics often used for specific bacteria include:

For Staphylococcus aureus, including MRSA: Vancomycin, daptomycin, or linezolid. For Streptococcus species: Penicillin or ceftriaxone. For Escherichia coli and other Gram-negative bacteria: Ceftriaxone, cefotaxime, or fluoroquinolones.

Duration of Treatment

The duration of antibiotic therapy typically ranges from 6 to 12 weeks or longer, depending on the severity of the infection, the response to treatment, and the presence of complications. Prolonged treatment is often necessary to ensure complete eradication of the infection and to prevent relapse.

The appropriate duration of parenteral antibiotic treatment in patients with pyogenic spondylodiscitis after surgical intervention could be guided by the risk factors. The duration of postoperative intravenous antibiotic therapy could be reduced to 3 weeks for patients without positive blood culture or abscess formation 2)

Intravenous to Oral Transition

Intravenous to Oral Transition: In some cases, patients may be transitioned from intravenous to oral antibiotics once they show clinical improvement and are stable. This transition is based on the patient’s clinical response and the recommendations of the healthcare team.

Monitoring

Monitoring: Close monitoring of the patient’s clinical progress, laboratory markers of infection (such as C-reactive protein and erythrocyte sedimentation rate), and imaging studies is essential to assess treatment efficacy and identify any complications.

It’s important for patients to complete the full course of antibiotics as prescribed to prevent relapse and the development of antibiotic resistance.

A nationwide survey of empiric antibiotic treatment for pyogenic spondylodiscitis revealed a large heterogeneity in the standard of care. A combination of a broad-spectrum-β-lactam antibiotic with an additional glycopeptide antibiotic may be justified 3)

Empirical broad-spectrum antibiotic therapy is linked to increased rates of complications such as Clostridium difficile-associated diarrhea and higher healthcare costs 4), and should be reserved for patients presenting with severe sepsis once blood cultures have been taken.

Test

Question 1: Which of the following is NOT an indication for surgical treatment in spondylodiscitis?

A) Neurologic deficits B) Sepsis C) Intraspinal empyema D) Positive blood culture

Question 2: Why might empirical antibiotic therapy be initiated before the exact microorganism is identified in spondylodiscitis?

A) To prevent antibiotic resistance B) To reduce the duration of antibiotic treatment C) To avoid potential side effects of antibiotics D) To provide immediate treatment while awaiting culture results

Question 3: Which of the following is a commonly implicated bacterium in pyogenic spondylodiscitis?

A) Candida albicans B) Escherichia coli C) Mycobacterium tuberculosis D) Streptococcus pneumoniae

Question 4: What is the typical duration of antibiotic therapy for spondylodiscitis?

A) 1-2 weeks B) 2-4 weeks C) 4-6 weeks D) 6-12 weeks or longer

Question 5: Under what circumstances can intravenous antibiotic therapy be reduced to 3 weeks after surgical intervention in spondylodiscitis?

A) Positive blood culture B) Abscess formation C) Clinical improvement D) All of the above

Question 6: When might a patient with spondylodiscitis be transitioned from intravenous to oral antibiotics?

A) Immediately upon diagnosis B) After surgical intervention C) Once blood cultures are taken D) When they show clinical improvement and are stable

Question 7: Why is close monitoring of patients with spondylodiscitis essential during treatment?

A) To assess treatment efficacy B) To prevent antibiotic resistance C) To reduce healthcare costs D) To guide surgical interventions

Question 8: What should patients do to prevent relapse and the development of antibiotic resistance during spondylodiscitis treatment?

A) Start antibiotic treatment as soon as possible B) Take antibiotics until they feel better C) Complete the full course of antibiotics as prescribed D) Reduce the antibiotic dose gradually

Question 9: In what situation might a combination of a broad-spectrum-β-lactam antibiotic with an additional glycopeptide antibiotic be justified in spondylodiscitis treatment?

A) In all cases B) When blood cultures are negative C) In patients with severe sepsis once blood cultures have been taken D) In patients with mild infection

Question 10: What is the potential drawback of starting empirical broad-spectrum antibiotic therapy in spondylodiscitis?

A) Reduced treatment efficacy B) Increased rates of Clostridium difficile-associated diarrhea C) Lower healthcare costs D) Shorter hospital stays

Answers:

D) Positive blood culture D) To provide immediate treatment while awaiting culture results B) Escherichia coli D) 6-12 weeks or longer D) All of the above D) When they show clinical improvement and are stable A) To assess treatment efficacy C) Complete the full course of antibiotics as prescribed C) In patients with severe sepsis once blood cultures have been taken B) Increased rates of Clostridium difficile-associated diarrhea

1)

Herren C, Jung N, Pishnamaz M, Breuninger M, Siewe J, Sobottke R. Spondylodiscitis: Diagnosis and Treatment Options. Dtsch Arztebl Int. 2017 Dec 25;114(51-52):875-882. doi: 10.3238/arztebl.2017.0875. PMID: 29321098; PMCID: PMC5769318.
2)

Li YD, Wong CB, Tsai TT, Lai PL, Niu CC, Chen LH, Fu TS. Appropriate duration of post-surgical intravenous antibiotic therapy for pyogenic spondylodiscitis. BMC Infect Dis. 2018 Sep 17;18(1):468. doi: 10.1186/s12879-018-3377-1. PMID: 30223785; PMCID: PMC6142394.
3)

Lang S, Walter N, Neumann C, Bärtl S, Simon M, Ehrenschwender M, Hitzenbichler F, Alt V, Rupp M. Aktuelle Praxis der empirischen Antibiotikatherapie bei Spondylodiszitis [Current practice of empiric antibiotic treatment for spondylodiscitis]. Orthopadie (Heidelb). 2022 Jul;51(7):540-546. German. doi: 10.1007/s00132-022-04240-x. Epub 2022 Apr 7. PMID: 35391543; PMCID: PMC9249703.
4)

Lillie P, Thaker H, Moss P, et al. Healthcare-associated discitis in the era of antimicrobial resistance. J Clin Rheumatol 2008;14:234-7.

Magnetic resonance imaging for idiopathic intracranial hypertension diagnosis

Magnetic resonance imaging for idiopathic intracranial hypertension diagnosis

Magnetic Resonance Imaging (MRI) plays an essential role in idiopathic intracranial hypertension diagnosis.

When evaluating a patient suspected of having IIH, MRI is commonly used for the following purposes:

Exclude Other Causes: An MRI of the brain is performed to rule out other conditions that may present with similar symptoms. These may include brain tumors, venous sinus thrombosis, or other intracranial abnormalities.

Assessment of the Brain and Ventricular System: MRI provides detailed images of the brain and can show any structural abnormalities, such as brain masses, cysts, or hydrocephalus (abnormal accumulation of cerebrospinal fluid). These findings can help identify or rule out potential causes of increased intracranial pressure.

Visualization of the Optic Nerves: MRI allows for visualization of the optic nerves and can detect any swelling or abnormalities, which can be crucial in diagnosing IIH. Enlargement of the subarachnoid space around the optic nerves (perioptic subarachnoid space distension) is a common finding in IIH.

Measurement of the Cerebral Venous Sinuses: MRI can assess the patency and flow within the cerebral venous sinuses, which are large blood vessels that drain blood from the brain. Abnormalities in these sinuses may contribute to IIH.

Assessment of Intracranial Pressure and Blood Flow: Specialized MRI techniques, such as MR venography and phase-contrast imaging, can be used to indirectly estimate intracranial pressure and evaluate cerebrospinal fluid (CSF) dynamics.

Follow-up and Monitoring: MRI may be used to monitor the progression of the condition and the effectiveness of treatment over time.

It’s important to note that while MRI is an essential diagnostic tool, the diagnosis of IIH typically involves a combination of clinical evaluation, neuroimaging, and other tests, such as lumbar puncture (to measure CSF pressure) and visual field testing (to assess any impact on vision).

MRI and magnetic resonance venography findings are important tools in the diagnosis of IIH. Empty sella turcica, optic nerve protrusion, distension of the optic nerve sheath, optic nerve tortuosity, posterior globe flattening, and transverse sinus stenosis have been found to be the most promising diagnostic markers for IIH, although the absence of these findings does not rule out the diagnosis 1).

Bsteh et al. included patients from the Vienna-Idiopathic-Intracranial-Hypertension (VIIH) database with Idiopathic intracranial hypertension according to Friedman criteria and cranial MRI performed at diagnosis. The presence of empty sella (ES), perioptic subarachnoid space distension (POSD) with or without optic nerve tortuosity (ONT), posterior globe flattening (PGF) and transverse sinus stenosis (TSS) was assessed and multivariable regression models regarding visual outcome (persistent visual impairment/visual worsening) and headache outcome (headache improvement/freedom of headache) were fitted.

They included 84 IIH patients (88.1% female, mean age 33.5 years, median body mass index 33.7). At baseline, visual impairment was present in 70.2% and headache in 84.5% (54.8% chronic). Persistent visual impairment occurred in 58.3%, visual worsening in 13.1%, headache improvement was achieved in 83.8%, and freedom of headache in 26.2%. At least one MRI feature was found in 78.6% and 60.0% had ≥3 features with POSD most frequent (64.3%) followed by TSS (60.0%), ONT (46.4%), ES (44.0%), and PGF (23.8%). In multivariable models, there was no association of any single MRI feature or their number with visual impairment, visual worsening, headache improvement, or freedom. Visual impairment at baseline predicted persistent visual impairment (odds ratio 6.3, p<0.001), but not visual worsening. Chronic headache at baseline was significantly associated with a lower likelihood of headache freedom (odds ratio 0.48, p=0.013), but not with headache improvement.

MRI features of IIH are neither prognostic of visual nor headache outcome 2).

In a retrospective, observational study included demographic and clinical data from 10 patients with IIH and 10 controls. Brain MRI findings in IIH patients were recorded twice: once when patients had papilledema and again after resolution of papilledema. Neuroradiologists graded MRI findings in both groups based on an imaging grading scale.

Results: After the resolution of papilledema, all patients showed improvement in 2 or more of the MRI characteristics of IIH. This was especially the case for the height of the midsagittal pituitary gland and optic nerve sheath thickness (ONST), which were significantly different in all pairwise group comparisons. Sellar configuration, globe configuration, and horizontal orbital optic nerve tortuosity were different between the IIH pre-treatment group and controls, but not between controls and the IIH post-treatment group. We found no difference in optic nerve head hyperintensity or optic nerve thickness among the 3 groups.

demonstrated that several morphometric MRI characteristics in IIH are reversible to a certain extent after treatment. Enlarged subarachnoid spaces filled with cerebrospinal fluid seem to remain reduced, and the ONST and height of the pituitary gland are not fully normalized after treatment 3)

Neuroimaging, usually with computed tomography (CT/CAT) or magnetic resonance imaging (MRI), is used to exclude any mass lesions. In IIH these scans typically appear to be normal, although small or slit-like ventricles, dilatation and buckling of the optic nerve sheaths and “empty sella sign” (flattening of the pituitary gland due to increased pressure) and enlargement of Meckel’s caves may be seen.

pedclerk.bsd.uchicago.edu_sites_pedclerk.uchicago.edu_files_uploads_pseudotumor_0.jpg

https://pedclerk.bsd.uchicago.edu/sites/pedclerk.uchicago.edu/files/uploads/pseudotumor_0.jpg

The protocol consists of a brain MRI and head magnetic resonance venography (MRV), both performed without and with intravenous gadolinium contrast material to minimize potential pitfalls of noncontrast MRV techniques and obviate ionizing radiation from CT/CT venography. Although low-field-strength MRI scanners may be sufficient to exclude large intracranial pathology, higher field strength (1.5 or 3.0 T) superconducting units are generally preferred to appreciate the imaging findings associated with chronically elevated ICP 4).

Magnetic resonance venography

see Magnetic resonance venography for idiopathic intracranial hypertension.

1)

Barkatullah AF, Leishangthem L, Moss HE. MRI findings as markers of idiopathic intracranial hypertension. Curr Opin Neurol. 2021 Feb 1;34(1):75-83. doi: 10.1097/WCO.0000000000000885. PMID: 33230036; PMCID: PMC7856277.
2)

Bsteh G, Marik W, Krajnc N, Macher S, Mitsch C, Pruckner P, Novak K, Wöber C, Pemp B. MRI features of idiopathic intracranial hypertension are not prognostic of visual and headache outcome. J Headache Pain. 2023 Jul 28;24(1):97. doi: 10.1186/s10194-023-01641-x. PMID: 37507663.
3)

Batur Caglayan HZ, Ucar M, Hasanreisoglu M, Nazliel B, Tokgoz N. Magnetic Resonance Imaging of Idiopathic Intracranial Hypertension: Before and After Treatment. J Neuroophthalmol. 2019 Sep;39(3):324-329. doi: 10.1097/WNO.0000000000000792. PMID: 31430269.
4)

https://academic.oup.com/neurosurgery/article/80/3/341/2901909/Imaging-of-Intracranial-Pressure-Disorders

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 mortality. Dexamethasone (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 multicenter, open-label, controlled, noninferiority 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.

Traumatic brain injury treatment

Traumatic brain injury treatment

Acute activation of innate immune response in the brain, or neuroinflammation, protects this vital organ from a range of external pathogens and promotes healing after traumatic brain injury.

Secondary brain injury treatment

see Secondary brain injury treatment

Transfer

Traumatic brain injury transfer.

Management in Emergency Room

Blood pressure and oxygenation

Level II: monitor BP and avoid hypotension (SBP <90 mm Hg).

Level III: monitor oxygenation and avoid hypoxia (PaO2 <60mm Hg or O2 saturation <90%).

Hypotension

Hypotension (shock) is rarely attributable to head injury except:

● in terminal stages (i.e. with dysfunction of medulla and cardiovascular collapse)

● in infancy, where enough blood can be lost intracranially or into the subgaleal space to cause shock

● where enough blood has been lost from scalp wounds to cause hypovolemia (exsanguination)

Hypotension (defined as a single SBP < 90 mm Hg) doubles mortality, hypoxia (apnea or cyanosis in the field, or PaO2 <60 mm Hg on ABG) also increases mortality, and the combination of both triples mortality and increases the risk bad outcome. SBP<90 mm Hg may impair CBF and exacerbate brain injury and should be avoided.

Early use of paralytics and sedation (prior to ICP monitoring)

see Sedative for traumatic brain injury.

Intubation and hyperventilation

Indications for intubation in trauma:

1. depressed level of consciousness (patient cannot protect airway): usually GCS≤7

2. need for hyperventilation (HPV).

3. severe maxillofacial trauma: patency of airway tenuous or concern for inability to maintain patency with further tissue swelling and/or bleeding

4. need for pharmacologic paralysis for evaluation or management.

There are currently no established treatments for the underlying pathophysiology in TBI and while neurorehabilitation efforts are promising, there are currently is a lack of consensus regarding rehabilitation following TBI of any severity 1).

Ask for Alcohol consumption

see Alcohol withdrawal syndrome

see Wernicke’s encephalopathy.

Neuroprotection for Traumatic Brain Injury

Neuroprotection for Traumatic Brain Injury

Severe traumatic brain injury treatment

see Severe traumatic brain injury treatment.

Pediatric traumatic brain injury guidelines

Pediatric traumatic brain injury guidelines.

Traumatic brain injury treatment during the Covid-19 pandemic

Treating traumatic brain injuries (TBIs) during the Covid-19 pandemic requires careful considerations to ensure the safety and well-being of both patients and healthcare providers. Here are some important aspects to consider in TBI treatment during the pandemic:

Emergency care: In the event of a severe TBI, emergency medical services and hospitals continue to provide critical care. Protocols are in place to protect both patients and healthcare workers from potential exposure to the virus.

Hospital precautions: Hospitals have implemented infection control measures to minimize the risk of Covid-19 transmission. These measures include screening patients for symptoms, providing personal protective equipment (PPE) to staff, isolating Covid-19-positive patients, and maintaining enhanced cleaning and disinfection procedures.

Rehabilitation services: Rehabilitation is an essential component of TBI treatment. During the pandemic, rehabilitation facilities have implemented safety measures, such as reduced capacity, enhanced cleaning protocols, physical distancing measures, and telehealth options when appropriate.

Telehealth services: Telehealth has played a crucial role in providing ongoing care and support for TBI patients during the pandemic. Telehealth appointments allow healthcare providers to assess patients remotely, provide guidance, monitor progress, and offer therapy sessions when in-person visits are not feasible.

Mental health support: The Covid-19 pandemic has had a significant impact on mental health. It is crucial to address the emotional and psychological well-being of TBI patients, as they may face additional challenges and increased stress during these times. Teletherapy and virtual support groups can be valuable resources for providing mental health support.

Caregiver support: Caregivers play a vital role in supporting individuals with TBIs. They may face additional burdens and challenges during the pandemic. Providing caregiver support through virtual resources, educational materials, and online support groups can help them navigate these difficult circumstances.

Follow-up care: Regular follow-up appointments with healthcare providers are crucial for monitoring TBI recovery progress and addressing any ongoing concerns. Telehealth visits can be utilized for routine check-ups, medication management, and addressing non-emergency issues.

It is important to note that the specific guidelines and protocols for TBI treatment during the Covid-19 pandemic may vary depending on the location, healthcare facility, and individual circumstances.

1)

Marklund N, Bellander BM, Godbolt A, Levin H, McCrory P, Thelin EP. Treatments and rehabilitation in the acute and chronic state of traumatic brain injury. J Intern Med. 2019 Mar 18. doi: 10.1111/joim.12900. [Epub ahead of print] PubMed PMID: 30883980.

Craniopharyngioma endoscopic endonasal approach

Craniopharyngioma endoscopic endonasal approach

Latest Craniopharyngioma endoscopic endonasal approach PubMed-related Articles

Indications

Craniopharyngioma endoscopic endonasal approach Indications.

Systematic reviews

The endoscopic endonasal approach (EEA) for craniopharyngiomas has proven to be a safe option for extensive tumor resection, with minimal or no manipulation of the optic nerves and excellent visualization of the superior hypophyseal artery branches when compared to the Transcranial Approach (TCA). However, there is an ongoing debate regarding the criteria for selecting different approaches. To explore the current results of EEA and discuss its role in the management of craniopharyngiomas, Figueredo et al. performed MEDLINE, Embase, and LILACS searches from 2012 to 2022. Baseline characteristics, the extent of resection, and clinical outcomes were evaluated. Statistical analysis was performed through an X2 and Fisher exact test, and a comparison between quantitative variables through a Kruskal-Wallis and verified with post hoc Bonferroni. The tumor volume was similar in both groups (EEA 11.92 cm3, -TCA 13.23 cm3). The mean follow-up in months was 39.9 for EEA and 43.94 for TCA, p = 0.76). The EEA group presented a higher visual improvement rate (41.96% vs. 25% for TCA, p < 0.0001, OR 7.7). Permanent DI was less frequent with EEA (29.20% vs. 67.40% for TCA, p < 0.0001, OR 0.2). CSF Leaks occurred more frequently with EEA (9.94% vs. 0.70% for TCA, p < 0.0001, OR 15.8). Recurrence rates were lower in the EEA group (EEA 15.50% vs. for TCA 21.20%, p = 0.04, OR 0.7). The results demonstrate that, in selected cases, EEA for resection of craniopharyngiomas is associated with better results regarding visual preservation and extent of tumor resection. Postoperative cerebrospinal fluid fistula rates associated with EEA have improved compared to the historical series. The decision-making process should consider each person’s characteristics; however, it is noticeable that recent data regarding EEA justify its widespread application as a first-line approach in centers of excellence for skull base surgery 1).

Qiao et al., conducted a systematic review and meta-analysis. They conducted a comprehensive search of PubMed to identify relevant studies. Pituitary, hypothalamus functions and recurrence were used as outcome measures. A total of 39 cohort studies involving 3079 adult patients were included in the comparison. Among these studies, 752 patients across 17 studies underwent endoscopic transsphenoidal resection, and 2327 patients across 23 studies underwent transcranial resection. More patients in the endoscopic group (75.7%) had visual symptoms and endocrine symptoms (60.2%) than did patients in the transcranial group (67.0%, p = 0.038 and 42.0%, p = 0.016). There was no significant difference in hypopituitarism and pan-hypopituitarism after surgery between the two groups: 72.2% and 43.7% of the patients in endoscopic group compared to 80.7% and 48.3% in the transcranial group (p = 0.140 and p = 0.713). We observed same proportions of transient and permanent diabetes insipidus in both groups. Similar recurrence was observed in both groups (p = 0.131). Pooled analysis showed that neither weight gain (p = 0.406) nor memory impairment (p = 0.995) differed between the two groups. Meta-regression analysis revealed that gross total resection contributed to the heterogeneity of recurrence proportion (p < 0.001). They observed similar proportions of endocrine outcomes and recurrence in both endoscopic and transcranial groups. More recurrences were observed in studies with lower proportions of gross total resection 2).

Komotar et al performed a systematic review of the available published reports after endoscope-assisted endonasal approaches and compared their results with transsphenoidal purely microscope-based or transcranial microscope-based techniques.

The endoscopic endonasal approach is a safe and effective alternative for the treatment of certain craniopharyngiomas. Larger lesions with more lateral extension may be more suitable for an open approach, and further follow-up is needed to assess the long-term efficacy of this minimal access approach 3)

Nowadays, an endoscopic endonasal approach (EEA) provides an “easier” way for CPs resection allowing a direct route to the tumor with direct visualization of the surrounding structures, diminishing inadvertent injuries, and providing a better outcome for the patient 4).

Historically, aggressive surgical resection was the treatment goal to minimize the risk of tumor recurrence via open transcranial midline, anterolateral, and lateral approaches, but could lead to clinical sequela of visual, endocrine, and hypothalamic dysfunction. However, recent advances in the endoscopic endonasal approach over the last decade have mostly supplanted transcranial surgery as the optimal surgical approach for these tumors. With viable options for adjuvant radiation therapy, targeted medical treatment, and alternative minimally invasive surgical approaches, the management paradigm for craniopharyngiomas has shifted from aggressive open resection to more minimally invasive but maximally safe resection, emphasizing quality of life issues, particularly in regards to visual, endocrine, and hypothalamic function. 5).

Craniopharyngioma surgery has evolved over the last two decades. Traditional transcranial microsurgical approaches were the only option until the advent of the endoscopic endonasal approach 6).

The endoscopic endonasal approach for craniopharyngiomas is increasingly used as an alternative to microsurgical transsphenoidal or transcranial approaches. It is a step forward in treatment, providing improved resection rates and better visual outcome. Especially in retrochiasmatic tumors, this approach provides better lesion access and reduces the degree of manipulations of the optic apparatus. The panoramic view offered by endoscopy and the use of angulated optics allows the removal of lesions extending far into the third ventricle avoiding microsurgical brain splitting. Intensive training is required to perform this surgery 7).

The highest priority of current surgical craniopharyngioma treatment is to maximize tumor removal without compromising the patients’ long-term functional outcome. Surgical damage to the hypothalamus may be avoided or at least ameliorated with a precise knowledge regarding the type of adherence for each case.

Endoscopic endonasal approach, has been shown to achieve higher rates of hypothalamic preservation regardless of the degree of involvement by tumor 8) 9).

Extended endoscopic transsphenoidal approach have gained interest. Surgeons have advocated for both approaches, and at present there is no consensus whether one approach is superior to the other.

With the widespread use of endoscopes in endonasal surgery, the endoscopic transtuberculum transplanum approach have been proposed as an alternative surgical route for removal of different types of suprasellar tumors, including solid craniopharyngiomas in patients with normal pituitary function and small sella.

As part of a minimally disruptive treatment paradigm, the extended endoscopic transsphenoidal approach has the potential to improve rates of resection, improve postoperative visual recovery, and minimize surgical morbidity 10).

Corridors

The endoscopic endonasal approach has become a valid surgical technique for the management of craniopharyngiomas. It provides an excellent corridor to infra- and supradiaphragmatic midline craniopharyngiomas, including the management of lesions extending into the third ventricle chamber. Even though indications for this approach are rigorously lesion based, the data confirm its effectiveness in a large patient series 11).

The endoscopic endonasal approach offers advantages in the management of craniopharyngiomas that historically have been approached via the transsphenoidal approach (i.e., purely intrasellar or intra-suprasellar infradiaphragmatic, preferably cystic lesions in patients with panhypopituitarism).

Use of the extended endoscopic endonasal approach overcomes the limits of the transsphenoidal route to the sella enabling the management of different purely suprasellar and retrosellar cystic/solid craniopharyngiomas, regardless of the sellar size or pituitary function 12).

They provide acceptable results comparable to those for traditional craniotomies. Endoscopic endonasal surgery is not limited to adults and actually shows higher resection rates in the pediatric population 13).

Infrachiasmatic corridor

Infrachiasmatic corridor

Complications

Craniopharyngioma endoscopic endonasal approach complications.

Case series

see Craniopharyngioma endoscopic endonasal approach case series.

References

1)

Figueredo LF, Martínez AL, Suarez-Meade P, Marenco-Hillembrand L, Salazar AF, Pabon D, Guzmán J, Murguiondo-Perez R, Hallak H, Godo A, Sandoval-Garcia C, Ordoñez-Rubiano EG, Donaldson A, Chaichana KL, Peris-Celda M, Bendok BR, Samson SL, Quinones-Hinojosa A, Almeida JP. Current Role of Endoscopic Endonasal Approach for Craniopharyngiomas: A 10-Year Systematic Review and Meta-Analysis Comparison with the Open Transcranial Approach. Brain Sci. 2023 May 23;13(6):842. doi: 10.3390/brainsci13060842. PMID: 37371322.
2)

Qiao N. Endocrine outcomes of endoscopic versus transcranial resection of craniopharyngiomas: A system review and meta-analysis. Clin Neurol Neurosurg. 2018 Apr 7;169:107-115. doi: 10.1016/j.clineuro.2018.04.009. [Epub ahead of print] Review. PubMed PMID: 29655011.
3)

Komotar RJ, Starke RM, Raper DM, Anand VK, Schwartz TH. Endoscopic endonasal compared with microscopic transsphenoidal and open transcranial resection of craniopharyngiomas. World Neurosurg. 2012 Feb;77(2):329-41. doi: 10.1016/j.wneu.2011.07.011. Epub 2011 Nov 1. Review. PubMed PMID: 22501020.
4)

Aragón-Arreola JF, Marian-Magaña R, Villalobos-Diaz R, López-Valencia G, Jimenez-Molina TM, Moncada-Habib JT, Sangrador-Deitos MV, Gómez-Amador JL. Endoscopic Endonasal Approach in Craniopharyngiomas: Representative Cases and Technical Nuances for the Young Neurosurgeon. Brain Sci. 2023 Apr 28;13(5):735. doi: 10.3390/brainsci13050735. PMID: 37239207; PMCID: PMC10216292.
5)

Hong CS, Omay SB. The Role of Surgical Approaches in the Multi-Modal Management of Adult Craniopharyngiomas. Curr Oncol. 2022 Feb 24;29(3):1408-1421. doi: 10.3390/curroncol29030118. PMID: 35323318; PMCID: PMC8947636.
6)

Fong RP, Babu CS, Schwartz TH. Endoscopic endonasal approach for craniopharyngiomas. J Neurosurg Sci. 2021 Apr;65(2):133-139. doi: 10.23736/S0390-5616.21.05097-9. PMID: 33890754.
7)

Baldauf J, Hosemann W, Schroeder HW. Endoscopic Endonasal Approach for Craniopharyngiomas. Neurosurg Clin N Am. 2015 Jul;26(3):363-75. doi: 10.1016/j.nec.2015.03.013. Epub 2015 May 26. PMID: 26141356.
8)

Tan TSE, Patel L, Gopal-Kothandapani JS, Ehtisham S, Ikazoboh EC, Hayward R, et al: The neuroendocrine sequelae of paediatric craniopharyngioma: a 40-year meta-data analysis of 185 cases from three UK centres. Eur J Endocrinol 176:359–369, 2017
9)

Yokoi H, Kodama S, Kogashiwa Y, Matsumoto Y, Ohkura Y, Nakagawa T, et al: An endoscopic endonasal approach for early-stage olfactory neuroblastoma: an evaluation of 2 cases with minireview of literature. Case Rep Otolaryngol 2015:541026, 2015
10)

Zacharia BE, Amine M, Anand V, Schwartz TH. Endoscopic Endonasal Management of Craniopharyngioma. Otolaryngol Clin North Am. 2016 Feb;49(1):201-12. doi: 10.1016/j.otc.2015.09.013. Review. PubMed PMID: 26614838.
11)

Cavallo LM, Frank G, Cappabianca P, Solari D, Mazzatenta D, Villa A, Zoli M, D’Enza AI, Esposito F, Pasquini E. The endoscopic endonasal approach for the management of craniopharyngiomas: a series of 103 patients. J Neurosurg. 2014 May 2. [Epub ahead of print] PubMed PMID: 24785324.
12)

Cavallo LM, Solari D, Esposito F, Villa A, Minniti G, Cappabianca P. The Role of the Endoscopic Endonasal Route in the Management of Craniopharyngiomas. World Neurosurg. 2014 Dec;82(6S):S32-S40. doi: 10.1016/j.wneu.2014.07.023. Review. PubMed PMID: 25496633.
13)

Koutourousiou M, Gardner PA, Fernandez-Miranda JC, Tyler-Kabara EC, Wang EW, Snyderman CH. Endoscopic endonasal surgery for craniopharyngiomas: surgical outcome in 64 patients. J Neurosurg. 2013 Nov;119(5):1194-207. doi: 10.3171/2013.6.JNS122259. Epub 2013 Aug 2. PubMed PMID: 23909243.

Vorasidenib

Vorasidenib

Vorasidenib (AG-881) is an orally available, brain-penetrant second-generation dual mutant isocitrate dehydrogenases 1 and 2 (mIDH1/2) inhibitor. Vorasidenib (AG-881) exhibits nanomolar inhibition of (D)-2-hydroxyglutarate (D-2-HG), and the IC50 ranges of 0.04~22 nM against IDH1 R132C, IDH1 R132G, IDH1 R132H and IDH1 R132S and 7~14 nM against IDH2 R140Q and 130 nM against IDH2 R172K

In a double-blind, phase 3 trial, Mellinghoff et al. randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary endpoint was imaging-based progression-free survival according to a blinded assessment by an independent review committee. The key secondary endpoint was the time for the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed.

A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or a placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P<0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P<0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received a placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo

In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention. (Funded by Servier; INDIGO ClinicalTrials.gov number, NCT04164901.). 1)

According to the phase III INDIGO trial, vorasidenib, an IDH1/2 inhibitor, significantly benefited adults with IDH1/2-mutant low-grade gliomas, reducing progression risk and delaying the need for chemoradiotherapy. Meanwhile, in a pediatric low-grade glioma cohort of FIREFLY-1, a phase II trial, robust responses to the type II pan-RAF inhibitor tovorafenib were seen 2)

Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDH glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of D-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1-97.6) and 91.1% (95% CrI, 72.0-97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of ‘proneural’ and ‘stemness’ gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197 3)

computational drug repurposing strategies were employed to identify potent mIDH1- specific inhibitors from the 11,808 small molecules listed in the DrugBank repository.

Methods: Tanimoto coefficient (Tc) calculations were initially used to retrieve compounds with structurally similar scaffolds to ivosidenib. The resultant compounds were then subjected to molecular docking to discriminate the binders from the non-binders. The binding affinities and pharmacokinetic properties of the screened compounds were examined using prime Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) and QikProp algorithm, respectively. The conformational stability of these molecules was validated using 100 ns molecular dynamics simulation.

Results: Together, these processes led to the identification of three-hit molecules, namely DB12001, DB08026, and DB03346, as potential inhibitors of the mIDH1 protein. Of note, the binding free energy calculations and MD simulation studies emphasized the greater binding affinity and structural stability of the hit compounds towards the mIDH1 protein.

Conclusion: The collective evidence from our study indicates the activity of DB12001 against recurrent glioblastoma, which, in turn, highlights the accuracy of our adapted strategy. Hence, we hypothesize that the identified lead molecules could be translated for the development of mIDH1 inhibitors in the near future 4)

Vorasidenib (AG-881) has recently been reported as a promising dual inhibitor of mutant isocitrate dehydrogenase 1 and 2 with the ability to penetrate the blood-brain barrier towards the treatment of low-grade glioma. In order to combat drug resistance and toxicity levels, this compelled us to further investigate this substance as a basis for the creation of potential selective inhibitors of mutant isocitrate dehydrogenases 1 and 2.

Methods: By employing a wide range of computational techniques, binding moieties of AG-881 that contributed towards its selective binding to isocitrate dehydrogenase enzymes 1 and 2 were identified and subsequently used to generate pharmacophore models for the screening of potential inhibitor drugs that were further assessed by their pharmacokinetics and physicochemical properties.

Results: AG-881 was identified as the most favorable candidate for isocitrate dehydrogenase enzyme 1, exhibiting a binding free energy of -28.69 kcal/mol. ZINC93978407 was the most favorable candidatefor isocitrate dehydrogenase enzyme 2, displaying a strong binding free energy of -27.10 kcal/mol. ZINC9449923 and ZINC93978407 towards isocitrate dehydrogenase enzyme 1 and 2 showed good protein structural stability with a low radius of gyration values relative to AG-881.

Conclusion: We investigated that ZINC9449923 of isocitrate dehydrogenase enzyme 1 and ZINC 93978407 of isocitrate dehydrogenase enzyme 2 could serve as promising candidates for the treatment of lower-grade glioma as they cross the blood-brain barrier, and present with lower toxicity levels relative to AG-881 5)

conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154.

Results: Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2-40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients.

Conclusions: Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing mIDH LGG 6).

A analysis proved that the dual-targeting ability of AG-881 is mediated by Val255/Val294 within the binding pockets of both mIDH1 and mIDH2 which are shown to elicit a strong intermolecular interaction, thus favoring binding affinity. The structural orientations of AG-881 within the respective hydrophobic pockets allowed favorable interactions with binding site residues which accounted for its high binding free energy of -28.69 kcal/mol and -19.89 kcal/mol towards mIDH1 and mIDH2, respectively. Interestingly, upon binding, AG-881 was found to trigger systemic alterations of mIDH1 and mIDH2 characterized by restricted residue flexibility and a reduction in exposure of residues to the solvent surface area. As a result of these structural alterations, crucial interactions of the mutant enzymes were inhibited, a phenomenon that results in a suppression of the production of oncogenic stimulator 2-HG. Findings therefore provide thorough structural and dynamic insights associated with the dual inhibitory activity of AG-881 towards glioma therapy 7)

Mutations in isocitrate dehydrogenase 1 (IDH1mut) are reported in 70-90% of low-grade gliomas and secondary glioblastomas. IDH1mut catalyzes the reduction of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), an oncometabolite which drives tumorigenesis. Inhibition of IDH1mut is therefore an emerging therapeutic approach, and inhibitors such as AG-120 and AG-881 have shown promising results in phase 1 and 2 clinical studies. However, detection of response to these therapies prior to changes in tumor growth can be challenging. The goal of this study was to identify non-invasive clinically translatable metabolic imaging biomarkers of IDH1mut inhibition that can serve to assess response. Methods: IDH1mut inhibition was confirmed using an enzyme assay and 1H- and 13C- magnetic resonance spectroscopy (MRS) were used to investigate the metabolic effects of AG-120 and AG-881 on two genetically engineered IDH1mut-expressing cell lines, NHAIDH1mut and U87IDH1mut. Results:1H-MRS indicated a significant decrease in steady-state 2-HG following treatment, as expected. This was accompanied by a significant 1H-MRS-detectable increase in glutamate. However, other metabolites previously linked to 2-HG were not altered. 13C-MRS also showed that the steady-state changes in glutamate were associated with a modulation in the flux of glutamine to both glutamate and 2-HG. Finally, hyperpolarized 13C-MRS was used to show that the flux of α-KG to both glutamate and 2-HG was modulated by treatment. Conclusion: In this study, we identified potential 1H- and 13C-MRS-detectable biomarkers of response to IDH1mut inhibition in gliomas. Although further studies are needed to evaluate the utility of these biomarkers in vivo, we expect that in addition to a 1H-MRS-detectable drop in 2-HG, a 1H-MRS-detectable increase in glutamate, as well as a hyperpolarized 13C-MRS-detectable change in [1-13C] α-KG flux, could serve as metabolic imaging biomarkers of response to treatment 8)

1)

Mellinghoff IK, van den Bent MJ, Blumenthal DT, Touat M, Peters KB, Clarke J, Mendez J, Yust-Katz S, Welsh L, Mason WP, Ducray F, Umemura Y, Nabors B, Holdhoff M, Hottinger AF, Arakawa Y, Sepulveda JM, Wick W, Soffietti R, Perry JR, Giglio P, de la Fuente M, Maher EA, Schoenfeld S, Zhao D, Pandya SS, Steelman L, Hassan I, Wen PY, Cloughesy TF. Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. N Engl J Med. 2023 Jun 4. doi: 10.1056/NEJMoa2304194. Epub ahead of print. PMID: 37272516.
2)

Targeted Options for Glioma Looking Good. Cancer Discov. 2023 Jun 5:OF1. doi: 10.1158/2159-8290.CD-ND2023-0004. Epub ahead of print. PMID: 37276325.
3)

Mellinghoff IK, Lu M, Wen PY, Taylor JW, Maher EA, Arrillaga-Romany I, Peters KB, Ellingson BM, Rosenblum MK, Chun S, Le K, Tassinari A, Choe S, Toubouti Y, Schoenfeld S, Pandya SS, Hassan I, Steelman L, Clarke JL, Cloughesy TF. Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial. Nat Med. 2023 Mar;29(3):615-622. doi: 10.1038/s41591-022-02141-2. Epub 2023 Feb 23. PMID: 36823302.
4)

Murali P, Karuppasamy R. Imidazole and Biphenyl Derivatives as Anti-cancer Agents for Glioma Therapeutics: Computational Drug Repurposing Strategy. Anticancer Agents Med Chem. 2023;23(9):1085-1101. doi: 10.2174/1871520623666230125090815. PMID: 36698225.
5)

Poonan P, Peters XQ, Soliman MES, Alahmdi MI, Abo-Dya NE. Pharmacophore-based Identification of Potential Mutant Isocitrate Dehydrogenases I/2 Inhibitors: An Explorative Avenue in Cancer Drug Design. Anticancer Agents Med Chem. 2023;23(8):953-966. doi: 10.2174/1871520623666221129163001. PMID: 36453510.
6)

Mellinghoff IK, Penas-Prado M, Peters KB, Burris HA 3rd, Maher EA, Janku F, Cote GM, de la Fuente MI, Clarke JL, Ellingson BM, Chun S, Young RJ, Liu H, Choe S, Lu M, Le K, Hassan I, Steelman L, Pandya SS, Cloughesy TF, Wen PY. Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial. Clin Cancer Res. 2021 Aug 15;27(16):4491-4499. doi: 10.1158/1078-0432.CCR-21-0611. Epub 2021 Jun 2. PMID: 34078652; PMCID: PMC8364866.
7)

Poonan P, Agoni C, Soliman MES. Dual-Knockout of Mutant Isocitrate Dehydrogenase 1 and 2 Subtypes Towards Glioma Therapy: Structural Mechanistic Insights on the Role of Vorasidenib. Chem Biodivers. 2021 May 12. doi: 10.1002/cbdv.202100110. Epub ahead of print. PMID: 33982420.
8)

Molloy AR, Najac C, Viswanath P, Lakhani A, Subramani E, Batsios G, Radoul M, Gillespie AM, Pieper RO, Ronen SM. MR-detectable metabolic biomarkers of response to mutant IDH inhibition in low-grade glioma. Theranostics. 2020 Jul 9;10(19):8757-8770. doi: 10.7150/thno.47317. PMID: 32754276; PMCID: PMC7392019.

Craniopharyngioma (CP)

Craniopharyngioma (CP)

A craniopharyngioma (CP) is an embryonic malformation of the sellar region and parasellar region.

Its relation to Rathke’s cleft cyst (RCC) is controversial, and both lesions have been hypothesized to lie on a continuum of ectodermal cystic lesions of the sellar region.

Jakob Erdheim (1874-1937) was a Viennese pathologist who identified and defined a category of pituitary tumors known as craniopharyngiomas. He named these lesions “hypophyseal duct tumors” (Hypophysenganggeschwülste), a term denoting their presumed origin from cell remnants of the hypophyseal duct, the embryological structure through which Rathke’s pouch migrates to form part of the pituitary gland. He described the two histological varieties of these lesions as the adamantinomatous and the squamous-papillary types. He also classified the different topographies of craniopharyngiomas along the hypothalamus-pituitary axis. Finally, he provided the first substantial evidence for the functional role of the hypothalamus in the regulation of metabolism and sexual functions. Erdheim’s monograph on hypophyseal duct tumors elicited interest in the clinical effects and diagnosis of pituitary tumors. It certainly contributed to the development of pituitary surgery and neuroendocrinology. Erdheim’s work was greatly influenced by the philosophy and methods of research introduced to the Medical School of Vienna by the prominent pathologist Carl Rokitansky. Routine practice of autopsies in all patients dying at the Vienna Municipal Hospital (Allgemeines Krankenhaus), as well as the preservation of rare pathological specimens in a huge collection stored at the Pathological-Anatomical Museum, represented decisive policies for Erdheim’s definition of a new category of epithelial hypophyseal growths. Because of the generalized use of the term craniopharyngioma, which replaced Erdheim’s original denomination, his seminal work on hypophyseal duct tumors is only referenced in passing in most articles and monographs on this tumor.

Jakob Erdheim should be recognized as the true father of craniopharyngiomas 1).

Epidemiology

Craniopharyngioma epidemiology.

Origin

Its relation to Rathke’s cleft cyst (RCC) is controversial, and both lesions have been hypothesized to lie on a continuum of cystic ectodermal lesions of the sellar region.

It grows close to the optic nerve, hypothalamus and pituitary gland.

Craniopharyngiomas frequently grow from remnants of the Rathke pouch, which is located on the cisternal surface of the hypothalamic region. These lesions can also extend elsewhere in the infundibulohypophyseal axis.

These tumors can also grow from the infundibulum or tuber cinereum on the floor of the third ventricle, developing exclusively into the third ventricle.

Classification

Craniopharyngioma Classification.

Molecular and genetic markers

Genetic and immunological markers show variable expression in different types of Craniopharyngioma. BRAF is implicated in tumorigenesis in papillary Craniopharyngioma (pCP), whereas CTNNB1 and EGFR are often overexpressed in adamantinomatous Craniopharyngioma (aCP) and VEGF is overexpressed in aCP and Craniopharyngioma recurrence. Targeted treatment modalities inhibiting thesepathways can shrink or halt progression of CP. In addition, Epidermal growth factor receptor tyrosine kinase inhibitors may sensitize tumors to radiation therapy. These – drugs show promise in medical management and neoadjuvant therapy for CP. Immunotherapy, including anti-interleukin 6 (IL-6) drugs and interferon treatment, are also effective in managing tumor growth. Ongoing – clinical trials in CP are limited but are testing BRAF/MET inhibitors and IL-6 monoclonal antibodies.

Genetic and immunological markers show variable expression in different subtypes of CP. Several current molecular treatments have shown some success in the management of this disease. Additional clinical trials and targeted therapies will be important to improve CP patient outcomes 2).

Craniopharyngioma Natural History

Craniopharyngioma natural history.

Clinical Features

see Craniopharyngioma Clinical Features.

Diagnosis

see Craniopharyngioma Diagnosis.

Differential diagnosis

Rathke’s cleft cyst.

ependymoma, pilocytic astrocytoma, choroid plexus papilloma (CPP), craniopharyngioma, primitive neuroectodermal tumor (PNET), choroid plexus carcinoma (CPC), immature teratoma, atypical teratoid rhabdoid tumor (AT/RT), anaplastic astrocytoma, and gangliocytoma.

Compared with craniopharyngiomas, sellar gliomas presented with a significantly lower ratio of visual disturbances, growth hormone deficiencies, lesion cystic changes, and calcification. Sellar gliomas had significantly greater effects on the patients’ mentality and anatomical brain stem involvement 3).

Co-occurrence

Simultaneous sellar-suprasellar craniopharyngioma and intramural clival chordoma, successfully treated by a single staged, extended, fully endoscopic endonasal approach, which required no following adjuvant therapy is reported 4).

Treatment

see Craniopharyngioma treatment

Outcome

see Craniopharyngioma outcome

Books

Craniopharyngioma: Surgical Treatment.

10 Selected Works

Craniopharyngioma Selected Works.

Case series

see Craniopharyngioma case series.

Case reports

see Craniopharyngioma case reports.

Videos

Craniopharyngioma Videos

1)

Pascual JM, Rosdolsky M, Prieto R, Strauβ S, Winter E, Ulrich W. Jakob Erdheim (1874-1937): father of hypophyseal-duct tumors (craniopharyngiomas). Virchows Arch. 2015 Jun 19. [Epub ahead of print] PubMed PMID: 26089144.
2)

Reyes M, Taghvaei M, Yu S, Sathe A, Collopy S, Prashant GN, Evans JJ, Karsy M. Targeted Therapy in the Management of Modern Craniopharyngiomas. Front Biosci (Landmark Ed). 2022 Apr 20;27(4):136. doi: 10.31083/j.fbl2704136. PMID: 35468695.
3)

Deng S, Li Y, Guan Y, Xu S, Chen J, Zhao G. Gliomas in the Sellar Turcica Region: A Retrospective Study Including Adult Cases and Comparison with Craniopharyngioma. Eur Neurol. 2014 Dec 18;73(3-4):135-143. [Epub ahead of print] PubMed PMID: 25531372.
4)

Iacoangeli M, Rienzo AD, Colasanti R, Scarpelli M, Gladi M, Alvaro L, Nocchi N, Scerrati M. A rare case of chordoma and craniopharyngioma treated by an endoscopic endonasal, transtubercular transclival approach. Turk Neurosurg.2014;24(1):86-9. doi: 10.5137/1019-5149.JTN.7237-12.0. PubMed PMID: 24535799.

Chronic subdural hematoma treatment

Chronic subdural hematoma treatment

Corticosteroids are associated with reduced recurrence but also increased morbidity. Drains reduce the risk of recurrence, but the position of drain (subdural vs subgaleal) did not influence recurrence. Middle meningeal artery embolization is a promising treatment warranting further evaluation in randomized trials 1).

Surgical therapies involve the irrigation and removal of the blood products, sometimes with partial resection of these vascular membranes 2).

Investigational medical therapies have employed various strategies, which include reducing the rate of microhemorrhage from the membranes, changing the osmotic environment, or altering angiogenesis 3).

Endovascular therapies are aimed at de-vascularizing these membranes 4) 5) 6) 7).

Providing a high level of evidence to propose a standard of care for this frequent pathology is of utmost importance. However, two surveys in the UK and in France have shown a wide range of practice, without major rationale 8) 9).

A variety of clinical factors must be taken into account in the treatment of chronic subdural hematoma (cSDH), and the multifaceted treatment paradigms continue to evolve 10).

There is lack of uniformity about the treatment strategies, such as the role of burr hole, twist drill, craniotomy, etc., in CSDH amongst various surgeons. There is also disagreement about the use of drain, irrigation, and steroid 11) 12).

Surgery is usually the treatment of choice, but conservative treatment may be a good alternative in some situations.

Chronic subdural hematoma surgery

see Chronic subdural hematoma surgery.

Middle Meningeal Artery Embolization

see Middle meningeal artery embolization for chronic subdural hematoma.

Systematic reviews

Chronic subdural hematoma recurrence after evacuation occurs in approximately 10% of chronic subdural hematomas, and the various Chronic subdural hematoma surgery interventions are approximately equivalent. Corticosteroids are associated with reduced recurrence but also increased morbidity. Drains reduce the risk of recurrence, but the position of drain (subdural vs subgaleal) did not influence recurrence. Middle meningeal artery embolization is a promising treatment warranting further evaluation in randomized trials 13).

Soleman et al., provide a systematic review of studies analysing the conservative treatment options and the natural history of cSDH. Of 231 articles screened, 35 were included in this systematic review. Studies evaluating the natural history and conservative treatment modalities of cSDH remain sparse and are predominantly of low level of evidence. The natural history of cSDH remains unclear and is analysed only in case reports or very small case series. “Wait and watch” or “wait and scan” management is indicated in patients with no or minor symptoms (Markwalder score 0-1). However, it seems that there are no clear clinical or radiological signs indicating whether the cSDH will resolve spontaneously or not (type C recommendation). In symptomatic patients who are not worsening or in a comatose state, oral steroid treatment might be an alternative to surgery (type C recommendation). Tranexamic acid proved effective in a small patient series (type C recommendation), but its risk of increasing thromboembolic events in patients treated with antithrombotic or anticoagulant medication is unclear. Angiotensin converting-enzyme inhibitors were evaluated only as adjuvant therapy to surgery, and their effect on the rate of recurrence remains debatable. Mannitol showed promising results in small retrospective series and might be a valid treatment modality (type C recommendation). However, the long treatment duration is a major drawback. Patients presenting without paresis can be treated with a platelet activating factor receptor antagonist (type C recommendation), since they seem to promote resolution of the haematoma, especially in patients with subdural hygromas or low-density haematomas on computed tomography. Lastly, atorvastatin seems to be a safe option for the conservative treatment of asymptomatic or mildly symptomatic cSDH patients (type C recommendation). In conclusion, the knowledge of the conservative treatment modalities for cSDH is sparse and based on small case series and low grade evidence. However, some treatment modalities seem promising even in symptomatic patients with large haematomas. Randomised controlled trials are currently underway, and will hopefully provide us with good evidence for or against the conservative treatment of cSDH 14).

Surveys

The aim of a study was to survey aspects of current practice in the UK and Ireland. A 1-page postal questionnaire addressing the treatment of primary (i.e. not recurrent) CSDH was sent to consultant SBNS members in March 2006. There were 112 responses from 215 questionnaires (52%). The preferred surgical technique was burr hole drainage (92%). Most surgeons prefer not to place a drain, with 27% never using one and 58% using drain only in one-quarter of cases or less. Only 11% of surgeons always place a drain, and only 30% place one in 75% of cases or more. The closed subdural-to-external drainage was most commonly used (91%) with closed subgaleal-to-external and subdural-to-peritoneal conduit used less often (3 and 4%, respectively). Only 5% of responders claimed to know the exact recurrence rate. The average perceived recurrence rate among the surgeons that never use drains and those who always use drains, was the same (both 11%). Most operations are performed by registrars (77%). Postoperative imaging is requested routinely by 32% of respondents and 57% of surgeons prescribe bed rest. Ninety four per cent surgeons employ conservative management in less than one-quarter of cases. Forty-two per cent of surgeons never prescribe steroids, 55% prescribe them to those managed conservatively. This survey demonstrates that there are diverse practices in the management of CSDH. This may be because of sufficiently persuasive evidence either does not exist or is not always taken into account. The current literature provides Class II and III evidence and there is a need for randomized studies to address the role of external drainage, steroids and postoperative bed rest 15).

Cenic et al. developed and administered a questionnaire to Canadian Neurosurgeons with questions relating to the management of chronic and subacute subdural hematoma. Our sampling frame included all neurosurgery members of the Canadian Neurosurgical Society.

Of 158 questionnaires, 120 were returned (response rate = 76%). The respondents were neurosurgeons with primarily adult clinical practices (108/120). Surgeons preferred one and two burr-hole craniostomy to craniotomy or twist-drill craniostomy as the procedure of choice for initial treatment of subdural hematoma (35.5% vs 49.5% vs 4.7% vs 9.3%, respectively). Craniotomy and two burr-holes were preferred for recurrent subdural hematomas (43.3% and 35.1%, respectively). Surgeons preferred irrigation of the subdural cavity (79.6%), use of a subdural drain (80.6%), and no use of anti-convulsants or corticosteroids (82.1% and 86.6%, respectively). We identified a lack of consensus with keeping patients supine following surgery and post-operative antibiotic use.

The survey has identified variations in practice patterns among Canadian Neurosurgeons with respect to treatment of subacute or chronic subdural hematoma (SDH). Our findings support the need for further prospective studies and clinical trials to resolve areas of discrepancies in clinical management and hence, standardize treatment regimens 16).

Steroids

Steroids for chronic subdural hematoma.

Goreisan

see Goreisan for chronic subdural hematoma

Chronic subdural hematoma seizure prophylaxis

see Chronic subdural hematoma seizure prophylaxis.

Anticoagulation resumption after chronic subdural hematoma

Anticoagulation resumption after chronic subdural hematoma.

References

1) , 13)

Henry J, Amoo M, Kissner M, Deane T, Zilani G, Crockett MT, Javadpour M. Management of Chronic Subdural Hematoma: A Systematic Review and Component Network Meta-analysis of 455 Studies With 103 645 Cases. Neurosurgery. 2022 Dec 1;91(6):842-855. doi: 10.1227/neu.0000000000002144. Epub 2022 Sep 28. PMID: 36170165.
2)

Markwalder TM . The course of chronic subdural hematomas after burr-hole craniostomy with and without closed-system drainage. Neurosurg Clin N Am 2000;11:541–6.doi:10.1016/S1042-3680(18)30120-7
3)

Sun TF , Boet R , Poon WS . Non-surgical primary treatment of chronic subdural haematoma: preliminary results of using dexamethasone. Br J Neurosurg 2005;19:327–33.doi:10.1080/02688690500305332
4)

Link TW , Boddu S , Marcus J , et al . Middle meningeal artery embolization as treatment for chronic subdural hematoma: a case series. Oper Neurosurg 2018;14:556–62.doi:10.1093/ons/opx154
5)

Link TW , Boddu S , Paine SM , et al . Middle meningeal artery embolization for chronic subdural hematoma: a series of 60 cases. Neurosurgery 2018;121.doi:10.1093/neuros/nyy521
6)

Link TW , Rapoport BI , Paine SM , et al . Middle meningeal artery embolization for chronic subdural hematoma: Endovascular technique and radiographic findings. Interv Neuroradiol 2018;24:455–62.doi:10.1177/1591019918769336
7)

Link TW , Schwarz JT , Paine SM , et al . Middle meningeal artery embolization for Chronic subdural hematoma recurrence: a case series. World Neurosurg 2018;118:e570–4.doi:10.1016/j.wneu.2018.06.241
8)

M. Guénot, Hématome sous-dural chronique. Introduction et résultats de l’enquête de la SFNC, Neurochirurgie 4 (2001) 459–460 https://doi.org/ NCHIR-11-2001-47- 5-0028-3770-101019-ART7.
9)

] T. Santarius, R. Lawton, P.J. Kirkpatrick, P.J. Hutchinson, The management of primary chronic subdural haematoma: a questionnaire survey of practice in the United Kingdom and the Republic of Ireland, Br. J. Neurosurg. 22 (2008) 529–534, https://doi.org/10.1080/02688690802195381.
10)

Sahyouni R, Goshtasbi K, Mahmoodi A, Tran DK, Chen JW. Chronic Subdural Hematoma: A Historical and Clinical Perspective. World Neurosurg. 2017 Dec;108:948-953. doi: 10.1016/j.wneu.2017.09.064. Epub 2017 Sep 19. Review. PubMed PMID: 28935548.
11) , 15)

Santarius T, Lawton R, Kirkpatrick PJ, Hutchinson PJ. The management of primary chronic subdural haematoma: a questionnaire survey of practice in the United Kingdom and the Republic of Ireland. Br J Neurosurg. 2008 Aug;22(4):529-34. doi: 10.1080/02688690802195381. PubMed PMID: 18686063.
12)

Cenic A, Bhandari M, Reddy K. Management of chronic subdural hematoma: a national survey and literature review. Can J Neurol Sci. 2005 Nov;32(4):501-6. PubMed PMID: 16408582.
14)

Soleman J, Noccera F, Mariani L. The conservative and pharmacological management of chronic subdural haematoma. Swiss Med Wkly. 2017 Jan 19;147:w14398. doi: smw.2017.14398. PubMed PMID: 28102879.
16)

Cenic A, Bhandari M, Reddy K. Management of chronic subdural hematoma: a national survey and literature review. Can J Neurol Sci. 2005 Nov;32(4):501-6. PubMed PMID: 16408582.

t

A variety of clinical factors must be taken into account in the treatment of chronic subdural hematoma (cSDH), and the multifaceted treatment paradigms continue to evolve 1).

There is lack of uniformity about the treatment strategies, such as the role of burr hole, twist drill, craniotomy, etc., in CSDH amongst various surgeons. There is also disagreement about the use of drain, irrigation, and steroid 2) 3).

Surgery is usually the treatment of choice, but conservative treatment may be a good alternative in some situations.

see DECSA trial.

see Middle Meningeal Artery Embolization.

Chronic subdural hematoma surgery

see Chronic subdural hematoma surgery.

Systematic reviews

Soleman et al., provide a systematic review of studies analysing the conservative treatment options and the natural history of cSDH. Of 231 articles screened, 35 were included in this systematic review. Studies evaluating the natural history and conservative treatment modalities of cSDH remain sparse and are predominantly of low level of evidence. The natural history of cSDH remains unclear and is analysed only in case reports or very small case series. “Wait and watch” or “wait and scan” management is indicated in patients with no or minor symptoms (Markwalder score 0-1). However, it seems that there are no clear clinical or radiological signs indicating whether the cSDH will resolve spontaneously or not (type C recommendation). In symptomatic patients who are not worsening or in a comatose state, oral steroid treatment might be an alternative to surgery (type C recommendation). Tranexamic acid proved effective in a small patient series (type C recommendation), but its risk of increasing thromboembolic events in patients treated with antithrombotic or anticoagulant medication is unclear. Angiotensin converting-enzyme inhibitors were evaluated only as adjuvant therapy to surgery, and their effect on the rate of recurrence remains debatable. Mannitol showed promising results in small retrospective series and might be a valid treatment modality (type C recommendation). However, the long treatment duration is a major drawback. Patients presenting without paresis can be treated with a platelet activating factor receptor antagonist (type C recommendation), since they seem to promote resolution of the haematoma, especially in patients with subdural hygromas or low-density haematomas on computed tomography. Lastly, atorvastatin seems to be a safe option for the conservative treatment of asymptomatic or mildly symptomatic cSDH patients (type C recommendation). In conclusion, the knowledge of the conservative treatment modalities for cSDH is sparse and based on small case series and low grade evidence. However, some treatment modalities seem promising even in symptomatic patients with large haematomas. Randomised controlled trials are currently underway, and will hopefully provide us with good evidence for or against the conservative treatment of cSDH 4).

Surveys

The aim of a study was to survey aspects of current practice in the UK and Ireland. A 1-page postal questionnaire addressing the treatment of primary (i.e. not recurrent) CSDH was sent to consultant SBNS members in March 2006. There were 112 responses from 215 questionnaires (52%). The preferred surgical technique was burr hole drainage (92%). Most surgeons prefer not to place a drain, with 27% never using one and 58% using drain only in one-quarter of cases or less. Only 11% of surgeons always place a drain, and only 30% place one in 75% of cases or more. The closed subdural-to-external drainage was most commonly used (91%) with closed subgaleal-to-external and subdural-to-peritoneal conduit used less often (3 and 4%, respectively). Only 5% of responders claimed to know the exact recurrence rate. The average perceived recurrence rate among the surgeons that never use drains and those who always use drains, was the same (both 11%). Most operations are performed by registrars (77%). Postoperative imaging is requested routinely by 32% of respondents and 57% of surgeons prescribe bed rest. Ninety four per cent surgeons employ conservative management in less than one-quarter of cases. Forty-two per cent of surgeons never prescribe steroids, 55% prescribe them to those managed conservatively. This survey demonstrates that there are diverse practices in the management of CSDH. This may be because of sufficiently persuasive evidence either does not exist or is not always taken into account. The current literature provides Class II and III evidence and there is a need for randomized studies to address the role of external drainage, steroids and postoperative bed rest 5).

Cenic et al. developed and administered a questionnaire to Canadian Neurosurgeons with questions relating to the management of chronic and subacute subdural hematoma. Our sampling frame included all neurosurgery members of the Canadian Neurosurgical Society.

Of 158 questionnaires, 120 were returned (response rate = 76%). The respondents were neurosurgeons with primarily adult clinical practices (108/120). Surgeons preferred one and two burr-hole craniostomy to craniotomy or twist-drill craniostomy as the procedure of choice for initial treatment of subdural hematoma (35.5% vs 49.5% vs 4.7% vs 9.3%, respectively). Craniotomy and two burr-holes were preferred for recurrent subdural hematomas (43.3% and 35.1%, respectively). Surgeons preferred irrigation of the subdural cavity (79.6%), use of a subdural drain (80.6%), and no use of anti-convulsants or corticosteroids (82.1% and 86.6%, respectively). We identified a lack of consensus with keeping patients supine following surgery and post-operative antibiotic use.

The survey has identified variations in practice patterns among Canadian Neurosurgeons with respect to treatment of subacute or chronic subdural hematoma (SDH). Our findings support the need for further prospective studies and clinical trials to resolve areas of discrepancies in clinical management and hence, standardize treatment regimens 6).

Glucocorticoids

Since glucocorticoids have been used for treatment of cSDH in 1962 their role is still discussed controversially in lack of evident data. On the basis of the ascertained inflammation cycle in cSDH dexamethasone will be an ideal substance for a short lasting, concomitant treatment protocol.

A study is designed as a double-blind randomized placebo-controlled trial 820 patients who are operated for cSDH and from the age of 25 years are included after obtaining informed consent. They are randomized for administration of dexamethasone (16-16-12-12-8-4 mg/d) or placebo (maltodextrin) during the first 48 hours after surgery. The type I error is 5% and the type II error is 20%. The primary endpoint is the reoperation within 12 weeks postoperative.

This study tests whether dexamethasone administered over 6 days is a safe and potent agent in relapse prevention for evacuated cSDH 7).

Chronic subdural hematoma seizure prophylaxis

see Chronic subdural hematoma seizure prophylaxis.

Anticoagulation resumption after chronic subdural hematoma

Anticoagulation resumption after chronic subdural hematoma.

References

1)

Sahyouni R, Goshtasbi K, Mahmoodi A, Tran DK, Chen JW. Chronic Subdural Hematoma: A Historical and Clinical Perspective. World Neurosurg. 2017 Dec;108:948-953. doi: 10.1016/j.wneu.2017.09.064. Epub 2017 Sep 19. Review. PubMed PMID: 28935548.
2) , 5)

Santarius T, Lawton R, Kirkpatrick PJ, Hutchinson PJ. The management of primary chronic subdural haematoma: a questionnaire survey of practice in the United Kingdom and the Republic of Ireland. Br J Neurosurg. 2008 Aug;22(4):529-34. doi: 10.1080/02688690802195381. PubMed PMID: 18686063.
3)

Cenic A, Bhandari M, Reddy K. Management of chronic subdural hematoma: a national survey and literature review. Can J Neurol Sci. 2005 Nov;32(4):501-6. PubMed PMID: 16408582.
4)

Soleman J, Noccera F, Mariani L. The conservative and pharmacological management of chronic subdural haematoma. Swiss Med Wkly. 2017 Jan 19;147:w14398. doi: smw.2017.14398. PubMed PMID: 28102879.
6)

Cenic A, Bhandari M, Reddy K. Management of chronic subdural hematoma: a national survey and literature review. Can J Neurol Sci. 2005 Nov;32(4):501-6. PubMed PMID: 16408582.
7)

Emich S, Richling B, McCoy MR, Al-Schameri RA, Ling F, Sun L, Wang Y, Hitzl W. The efficacy of dexamethasone on reduction in the reoperation rate of chronic subdural hematoma – the DRESH study: straightforward study protocol for a randomized controlled trial. Trials. 2014 Jan 6;15(1):6. doi: 10.1186/1745-6215-15-6. PubMed PMID: 24393328; PubMed Central PMCID: PMC3891985.

Trigeminal neuralgia

Trigeminal neuralgia

Latest Pubmed Related Articles

The facial pain syndrome known as trigeminal neuralgia was described more than 300 years ago 1).

Definition

Trigeminal neuralgia definition.

Epidemiology

see Trigeminal neuralgia epidemiology.

Classification

see Trigeminal neuralgia classification.

Pathogenesis

see Trigeminal neuralgia pathogenesis.

Pathophysiology

see Trigeminal neuralgia pathophysiology.

Natural History

Typical trigeminal neuralgia caused by microvascular compression of the trigeminal nerve root in the posterior fossa may become transformed over time into atypical trigeminal neuralgia, if left untreated. This transformation involves change in the character of pain and development of sensory impairment. Two representative cases are presented to support this theory.

If the theory of progressive change in character of pain and degree of sensory impairment in the course of otherwise typical trigeminal neuralgia is correct, trigeminal neuralgia, atypical neuralgia, and trigeminal neuropathic pain may represent different degrees of injury to the trigeminal nerve, therefore comprising a continuous spectrum rather than discrete diagnoses 2).

Clinical Features

Trigeminal neuralgia clinical features.

Scales

Barrow Neurological Institute Pain Scale.

Barrow Neurological Facial Numbness Scale.

Slavin KV. Commentary: Development and Evaluation of a Preoperative Trigeminal Neuralgia Scoring System to Predict Long-Term Outcome Following Microvascular Decompression. Neurosurgery. 2019 Dec 9. pii: nyz540. doi: 10.1093/neuros/nyz540. [Epub ahead of print] PubMed PMID: 31813971.

Diagnosis

Trigeminal neuralgia diagnosis.

Treatment

see Trigeminal neuralgia treatment.

Outcome

see Trigeminal neuralgia outcome.

Case series

see Trigeminal neuralgia case series.

Case reports

see Trigeminal neuralgia case reports.

1)

Lewy FH: The first authentic case of major trigeminal neuralgia and some comments on the history of this disease. Ann Med Hist 10:247–250, 1938.
2)

Burchiel KJ, Slavin KV. On the natural history of trigeminal neuralgia. Neurosurgery. 2000 Jan;46(1):152-4; discussion 154-5. Review. PubMed PMID: 10626945.