NEURO-ONCOLOGY
- Approach to nonspecific presentations
- Direct effect of tumor mass
- Vascular
- Seizure
- Paraneoplastic syndromes
- Iatrogenic
- Opportunistic CNS infections
- Unique to hematologic malignancies
- Nutritional/metabolic complications of advanced malignancy
- Podcast
- Questions & discussion
- Pitfalls
When approaching a patient with malignancy and neurological dysfunction, the following investigations may be considered:
labs
- Blood count; electrolytes including Ca/Mg/Phos; liver function tests.
- Uric acid if tumor lysis syndrome is possible (this is primarily relevant for aggressive, hematologic malignancies 📖).
- If on valproic acid: Ammonia level.
- If treated with a checkpoint inhibitor, or if there is a pituitary lesion: TSH, free T4, cortisol level.
- If immunosuppressed by chemotherapy, or demonstrating features of infection: Infectious workup, including blood cultures.
- If paraneoplastic syndrome suspected: Serum paraneoplastic antibody panel.
EEG
- Brain cancer is a risk factor for seizure or nonconvulsive status epilepticus.
imaging
- CT +/- CTA scan may reveal edema, hemorrhage, or hydrocephalus.
- MRI is more sensitive for a broader range of pathologies.
lumbar puncture
- Allows evaluation for infection or leptomeningeal carcinomatosis.
basics
- Tumor and associated edema may exert mass effect on surrounding tissues.
- Blockage of cerebral aqueducts may lead to obstructive hydrocephalus.
clinical manifestations
- (1) Manifestations related to ICP elevation:
- Headache is usually a central symptom. It is often exacerbated by coughing, straining, or lying down.(33896532)
- Nausea and emesis may occur.
- Elevated intracranial pressure may cause an abducens nerve (CN6) palsy, causing diplopia.(31483060)
- Mental status alteration.
- Plateau waves may occur, causing transient clinical deterioration (e.g., reduced consciousness, pupillary dilation, headaches, nausea/vomiting, and dysautonomia).📖
- (2) Additional focal neurological signs and symptoms may occur (which will vary depending on the location of the tumor).
management
- ⚠️ For asymptomatic or minimally symptomatic edema, no treatment may be needed.(32596758)
- (1) Dexamethasone for tumor-related vasogenic edema:
- Edema is often substantial, so rapid control may promptly improve symptoms.
- For symptomatic mass effect, a reasonable dose might be 10-20 mg IV as a loading dose, followed by 4-6 mg IV q6 as a maintenance dose.(33896532, 26704760, 34618757) Following improvement, it may be reasonable to taper the dose to a 4-8 mg total daily dose.(34619783) Consolidation into a once-daily dose in the morning helps avoid insomnia (noting that dexamethasone has a ~48-hour biological half-life).(32596758)
- One potential drawback is that steroid may obscure the subsequent diagnosis of lymphoma. If lymphoma is suspected and symptoms are manageable, steroid might be delayed until after a biopsy (although some recent data challenges this long-standing belief).(27468790) CNS lymphoma typically causes a homogeneously enhancing, supratentorial lesion that is frequently in the periventricular white matter – more on this in the next section.(26704760)
- Bevacizumab, an anti-VEGF antibody that stabilizes the blood-brain barrier, could be considered as a steroid-sparing agent to control edema (e.g., if steroid is contraindicated).(32596758) However, bevacizumab takes effect over days to weeks, which is of little immediate value in the ICU.(26704760)
- (2) Management of elevated intracranial pressure (ICP):
- This is overall similar to management of elevated intracranial pressure in other contexts.📖
- Hypertonic therapy may be used initially as a bridge (either towards tumor resection, or to provide time for steroid to work).
- (3) Neurosurgical interventions:
- External ventricular drainage 📖 may be necessary for management of obstructive hydrocephalus.
- Resection of the tumor may be indicated in some situations (e.g., solitary metastasis, or primary brain tumor).
Primary CNS lymphoma is important to consider prior to the initiation of steroid for CNS malignancy.
basics
- PCNSL is a type of non-Hodgkin lymphoma (NHL) confined to the brain and spine that is associated with Epstein-Barr virus (EBV) in the context of immunocompromise.(34623105)
- Some clinical points about PCNSL:
- (1) Administration of steroid may cause PCNSL to regress, rendering diagnosis challenging. This is often a concern when administering steroid to a patient with an undiagnosed brain mass and surrounding edema. If steroid is absolutely required for life-threatening herniation, then biopsy should be pursued within <24-48 hours.(33273169)
- (2) PCNSL can be difficult to differentiate from toxoplasmosis in some patients.
epidemiology
- PCNSL accounts for 4% of all newly diagnosed brain cancers, most often occurring among patients in their sixties to seventies.(33273169)
- Immunocompetent patients may be affected, but the risk is increased by immunocompromise, including:
- Transplant patients.
- HIV (most often when CD4 <50, but it can occur with any CD4 count).
clinical manifestations
- Clinical presentation may include headache, altered mental status, abnormal cognition, focal deficits, elevated intracranial pressure, and/or seizures.
- Symptoms usually evolve over a period of weeks to months.
laboratory evaluation
- Lumbar puncture should be performed if safe to do so (i.e., lack of mass effect that poses a risk of herniation).
- EBV PCR may be positive, especially in immunocompromised patients.
- Flow cytometry and immunoglobulin heavy-chain gene rearrangement studies may be helpful.
imaging
- PCNSL usually causes a large solitary lesion (but smaller, multifocal, and more heterogeneous lesions may occur in the context of immunocompromise).(34623100)
- The location is typically within the white matter or basal ganglia. Spread may occur across the corpus callosum or along the ependymal surfaces, sometimes producing a periventricular distribution.
- CT characteristics include being isodense or hyperdense (due to high cellularity).
- MRI characteristics include:
- T2/FLAIR isointense to hyperintense.
- Homogeneous contrast enhancement is classic among immunocompetent patients (but it may also be patchy or rim-enhancing among immunocompromised patients).
- Restricted diffusion indicating the densely cellular nature of the tumor.(26046515)
- Often a mild amount of surrounding vasogenic edema.
- Differentiation of PCNSL vs. toxoplasmosis is discussed here: 📖.
management
- Chemotherapy is the backbone of therapy (often methotrexate).
- After the diagnosis is secured, steroid may be very effective to treat edema.
- Immunosuppression should be treated if possible (e.g., antiretroviral therapy for HIV).
Pituitary apoplexy refers to expansion and dysfunction of the pituitary gland due to hemorrhage and/or infarction. This often occurs in the context of a preexisting pituitary adenoma, but it can occur in the absence of malignancy.
causes
- Pituitary adenoma:
- Apoplexy may occur if a pituitary adenoma undergoes sudden infarction, hemorrhage, or both. Increased volume of the adenoma exerts mass effect on the pituitary gland and surrounding tissue.
- Apoplexy may occur in 2-12% of patients with pituitary adenomas.(31471052)
- Pregnancy: Rising estrogen levels stimulate increased prolactin production, which may have various consequences:
- 1) A pre-existing pituitary adenoma may enlarge and potentially undergo pituitary apoplexy.
- 2) A previously normal gland may hypertrophy and undergo pituitary apoplexy within the first few days of delivery (Sheehan syndrome).
- Perioperative hypotension.
- Vasospasm.
- Head trauma.
symptoms
- Headache (73%):(31471052)
- Often retro-orbital, deep pain that is unlike prior headaches. Thunderclap headache can occur.
- Pain may be severe enough to cause nausea and vomiting.(Nelson, 2020) Half of patients have nausea.
- Meningismus frequently occurs.(32487899)
- Visual disturbance (68%).(31471052)
- Visual field loss in 50% of patients (e.g., homonymous hemianopsia).
- Cranial neuropathies may result from impingement on the cavernous sinuses (that surround the pituitary).
- Most commonly affected is CN-III, causing ptosis and blown pupil(s).
- Altered mental status can occur in 20%, ranging from encephalopathy to coma.(32487899, 31471052)
- Endocrine dysfunction (typically manifesting with adrenal crisis).
- ~70% have adrenal insufficiency.(Nelson, 2020)
- Diabetes insipidus may occur.
- 💡 Subacute pituitary apoplexy: Some patients may have a self-limited headache and present to the hospital several days later with adrenal crisis. Headache may not be a prominent symptom at the time of (delayed) presentation.(31471052)
evaluation: labs to consider
- Evaluation for adrenal insufficiency with cortisol level, ACTH level, and possibly an ACTH stimulation test (more on this here: 📖).
- TSH and free T4 levels.
- Prolactin level.
evaluation: radiology
- CT scan is often obtained initially. It may show patches of hyperdensity within the sella (due to acute hemorrhage).(35353348)
- MRI is the test of choice:
- Pituitary mass may be seen, with exertion of mass effect on nearby structures.
- Hemorrhage may be evident on SWI/GRE sequences.
- MR angiography is indicated if vasospasm or aneurysm may be involved (but gadolinium is contraindicated in pregnancy).
- (A pituitary protocol MRI may be optimal. 🌊)
management – medical aspects
- (1) Management/prevention of adrenal crisis:
- Patients are nearly always adrenally insufficient.
- Empiric steroid replacement should generally be initiated (e.g., with stress-dose steroid, such as hydrocortisone 50 mg IV q6hr).📖 This is especially important before surgery, since surgery could precipitate an adrenal crisis.
- (2) Sodium management:
- Hyponatremia may occur due to adrenal insufficiency, hypothyroidism, and/or SIADH.
- Hypernatremia may result from central diabetes insipidus. Central diabetes insipidus (DI) is rare, but this is important to watch for because it requires active management.📖
- (3) If the prolactin level suggests prolactinoma (>200 ug/L), cabergoline may be utilized as medical therapy.(31471052)
- (4) Other hormone supplementation may eventually become necessary (e.g., thyroid hormone). Thyroid replacement must be delayed until after initiation of hydrocortisone, to avoid provoking adrenal crisis.
management – surgical aspects
- Neurosurgery may be needed to manage mass effect (if there is significant cranial neuropathy or vision loss).
- If not performed urgently, surgery should typically be performed within a week of symptom onset.(Nelson, 2020) Patients often have a pituitary adenoma that requires resection (regardless of the presence of pituitary apoplexy).
epidemiology
- Spinal cord compression is common, affecting ~5-10% of patients with cancer.
- Common causes include lung, breast, prostate, renal cell, and colorectal cancer. Hematologic malignancies are another cause (e.g., non-Hodgkin lymphoma, multiple myeloma).(26704760, 28190444)
clinical manifestations
- (#1) Back pain:
- This is the frequent symptom (affecting ~90% of patients). Pain commonly precedes neurological deterioration.
- Pain may be localized to the back, or may radiate in the distribution of spinal roots.
- Pain is often exacerbated by coughing, straining, lying supine, or movement.
- Pain doesn't always correspond to the site of compression (e.g., T1-T6 compression may cause lumbosacral pain).(28190444)
- (#2) Sensory symptoms may occur before paralysis:
- (#3) Extremity weakness and sphincter dysfunction occur late:
- This is the most feared and potentially debilitating consequence.
- If diagnosis is delayed until well after paraplegia/quadriplegia occurs, functional recovery is rare.(31483060)
investigation
- Physical examination may show:
- The presence of a sensory level (although this may be misleading regarding the precise height of the lesion within the spine).(26704760)
- Initially, patients may have spinal shock resulting in reduced tone and hyporeflexia. However, eventually increased deep tendon reflexes and pathologic reflexes develop (e.g., Babinski sign).
- MRI is preferred over CT scan. Ideally the entire spine should be imaged, since a third of patients may have involvement at more than one level.(31483060)
treatment
- Steroid (typically 10 mg dexamethasone followed by 4 mg IV q6hr). The initial bolus dose of steroid is controversial, with literature describing a range between 10-100 mg of dexamethasone.(31483060)
- Surgical decompression or radiotherapy. Surgical decompression usually leads to more favorable survival and function, among patients able to tolerate surgery.(Wijdicks, 2019) This may depend on such factors as the radiosensitivity of the tumor and the patient's ability to tolerate surgery.
differential diagnosis of possible causes
- (1) Stroke unrelated to the tumor (e.g., stroke may result from atherosclerotic disease or cardioembolism). This may be indirectly promoted by tumor-induced hypercoagulability.
- (2) Vascular compression or infiltration by the tumor.
- (3) Cardioembolic events related to malignancy:
- Tumor embolism (especially intracardiac tumors).
- Nonbacterial thrombotic endocarditis (aka marantic endocarditis) may cause cardioembolic strokes, as a consequence of disseminated intravascular coagulation due to advanced adenocarcinoma.
- Bacterial endocarditis (related to immunosuppression from malignancy and chemotherapy).
- Deep vein thrombosis with paradoxical embolization to the brain via a patent foramen ovale.
- (4) Treatment-related effect:
- Radiation vasculopathy.
- Chemotherapy (stroke is associated with L-asparaginase, platinum-based treatments, or bevacizumab).(32487905)
- Surgical complication.
- (5) As a consequence of PRES.
- (6) Opportunistic CNS infection:
- Varicella zoster virus associated arteritis.
- Meningitis, including opportunistic (e.g., fungal).(33273175)
- Angioinvasive mold infection (aspergillus, mucormycosis).
imaging
- MRI may be difficult to interpret because some tumors themselves can cause restricted diffusion on diffusion-weighted images (e.g., high-grade gliomas and primary CNS lymphomas).(32596758)
management
- Overall, management is similar to the management of acute ischemic stroke in general. Intracranial mass lesion is a relative contraindication to thrombolysis (but this decision will be made by the stroke neurology team).
- If the stroke is due to local mass effect from the tumor, then treatment of the underlying cancer is required (as discussed above 📖).
common mechanisms
- Intratumoral hemorrhage
- Primary brain tumors: Most often glioblastoma multiforme (GBM) or oligodendroglioma.
- Metastatic brain tumors: Cancers most prone to bleeding are melanoma, renal cell carcinoma, choriocarcinoma, papillary thyroid carcinoma, and hepatocellular carcinoma (table above).(32596758) However, because lung and breast cancer are extremely common, intratumoral hemorrhage is most frequently encountered in the context of melanoma, lung, or breast carcinoma.
- Systemic coagulopathy, for example:
- Acute promyelocytic leukemia (APL) is notorious for causing early and devastating intracranial hemorrhages due to disseminated intravascular coagulation. Preemptive management of coagulopathy may avoid this complication, as discussed further here.📖
- Thrombocytopenia is common (e.g., due to bone marrow infiltration or chemotherapy).📖
- Angiogenesis inhibitors including bevacizumab increase risks of hemorrhage.(33273175)
- Radiation-induced vascular malformation.
- Acute ischemic stroke with hemorrhagic transformation (more on acute ischemic stroke above).
- Cerebral venous thrombosis with secondary hemorrhage (more on this below).
presentation
- Presentation is similar to that of other patients with intraparenchymal hemorrhage.
- The two most common presenting features are hemiparesis and headaches. Other common manifestations are nausea/vomiting, encephalopathy, seizure, and coma.(Nelson, 2020)
radiologic clues to differentiate from other intracerebral hemorrhages:
- Metastases tend to occur at the junction of the gray and white matter, so this may lead to lobar hemorrhages.(32299594)
- Edema:
- Edema out of proportion to hemorrhage.
- Edema present at an early time point, when hemorrhage-related edema wouldn't be expected.(32299594)
- Tumor features:
management
- Management is similar to the treatment of intracerebral hemorrhage in general.📖
- A few differences which may arise in the context of malignancy:
- Particular attention should be paid to any underlying coagulopathies. These should be evaluated and treated aggressively.📖
- Some patients may have mass effect due to a combination of hemorrhage plus vasogenic edema due to the tumor. In this context, steroid may be utilized to reduce vasogenic edema caused by the tumor (as discussed above 📖).(32596758)
- Surgical resection may be considered, especially for solitary lesions with associated mass effect. Patients with solitary brain metastases may occasionally be candidates for palliative resection (metastasectomy), even in the absence of hemorrhage.
common mechanisms
- Direct compression by the tumor.
- Hypercoagulable state indirectly induced by malignancy (especially leukemia).(33896532)
- L-asparaginase (causes depletion of asparagine, leading to reduced synthesis of endogenous anticoagulants such as protein C and protein S).
management 📖
- Treatment is generally similar to the treatment of cerebral venous thrombosis in other patients (e.g., anticoagulation).
- If the tumor is directly compressing a venous sinus, then additional therapies might be contemplated (e.g., steroid for vasogenic edema, surgical resection).
basics
- This is a rare malignancy wherein lymphoma cells proliferate predominantly within capillaries and venules, leading to tissue ischemia. It is a variant of diffuse large B-cell lymphoma.
- This is also known as intravascular lymphomatosis, malignant angioendotheliomatosis, and angiotropic large cell lymphoma.
- Presentation is variable and difficult to diagnose.
clinical manifestations
- Median age at diagnosis is 70, with a broad range from 34-90 years old.(30111607)
- (1) Constitutional symptoms occur in most patients (e.g., fevers, night sweats, weight loss).
- (2) Skin involvement is seen in ~40% of patients. A wide range of lesions may occur, including: painful indurated erythematous eruption, poorly circumscribed violaceous plaques, peau d'orange, large solitary plaques, painful blue-red palpable nodular discolorations, tumors, ulcerated nodules, small red palpable spots, and erythematous and desquamated plaques.(30111607)
- (3) Neurologic symptoms occur in ~35% of patients, with wide variation including:(35419156)
- Strokes, seizures, delirium, dementia.
- Cranial neuropathy, radiculopathy, transverse myelitis.
- Peripheral neuropathy, myopathy.
- Neuroimaging may show numerous ischemic/inflammatory foci, often raising a concern regarding the possibility of vasculitis or multiple sclerosis.(30111607) Microhemorrhages may be seen.
- (4) Endocrine organs may be involved (mostly pituitary, thyroid, and adrenal glands), with failure of one or more organ.(30111607)
- (5) Lung involvement may occur. CT findings may include various patterns:(30111607)
- Ground glass opacities are usually a predominant finding (occasionally with a reverse halo sign, or mosaic attenuation).
- Septal thickening is often seen. Multiple centrilobular nodules may occur.
- A variant is seen mostly in Asian countries that causes HLH (hemophagocytic lymphohistiocytosis) 📖.(30111607)
diagnosis
- Laboratory findings are nonspecific:
- Elevated LDH (lactate dehydrogenase), erythrocyte sedimentation rate, and C-reactive protein.
- Anemia, thrombocytopenia, and/or leukopenia may be seen.
- Tissue diagnosis is required:
- Ideally the biopsy should be performed prior to initiation of steroid, since steroid may rapidly reduce the yield.(32373273)
- Skin biopsy is the safest and easiest approach. Deep skin biopsies may be positive, even in the absence of skin lesions (vascular involvement is often seen in the underlying adipose tissue).
- Other sites may be sampled if skin biopsies are unrevealing (e.g., bone marrow, muscle, or adrenal glands).(35419156) Brain biopsy is the most invasive, so this might ideally be reserved for situations where other biopsies are negative.
management
- Management involves various combined chemotherapy regimens for lymphoma.
- Patients may respond to empiric high-dose steroid, which may cause diagnostic confusion in some cases.
seizure risk due to a brain tumor
- Several factors affect the risk of seizure:(32596758)
- (1) Tumor type (slower growing tumors are often more epileptogenic; see table below).
- (2) Tumor location:
- Supratentorial lesion (especially frontal, temporal, or insular cortex).(33273175)
- Cortical location.
- Multiple lesions.
- (3) Associated hemorrhage increases the risk of seizure (either microhemorrhage or macrohemorrhage).
mechanisms of seizure genesis in oncologic patients are potentially diverse, including:
- (1) Cortical irritation from the tumor itself.
- (2) Metabolic abnormalities.
- (3) Posterior reversible encephalopathy syndrome (PRES), which may occur as a complication of various chemotherapies.
- (4) Vascular events (e.g., intracerebral hemorrhage, venous sinus thrombosis).
- (5) Meningoencephalitis (e.g., infectious or drug-related).
- (6) Paraneoplastic limbic encephalitis.📖
- (7) Seizure threshold may be lowered due to chemotherapy, antibiotics, antidepressants, or other medications.
- (A more complete list of potential causes of seizure is here: 📖)
symptoms
- Clinically overt seizure may occur. The seizure is initially focal, but it may generalize very rapidly (obscuring its initially focal nature).
- Other presentations may include encephalopathy, spells, or fluctuating focal neurologic deficits.(33896532)
management
- Prophylactic therapy with antiepileptic medications is generally not recommended for patients with CNS malignancy.(33896532) However, prophylaxis is recommended in the first week following resection of supratentorial brain tumors, to prevent postoperative seizures.(32596758)
- Seizure is generally treated in a similar fashion compared to other patients. However, fosphenytoin, carbamazepine, phenobarbital, or valproic acid may interact with some chemotherapeutic regimens (table below). Alternatively, agents which are predominantly renally cleared tend to have fewer drug interactions (e.g., levetiracetam, lacosamide, clobazam, pregabalin, vigabatrin).(33273175) Levetiracetam is the most commonly utilized agent, with lacosamide being a reasonable second-line agent.(35353348; 28190444) Patients with tumor-associated epilepsy may have high rates of failure with first-line antiepileptic drugs, so multiple agents may be needed.(28190444)
- Brain tumor is a common cause of status epilepticus. This should be treated similarly to other patients with status epilepticus.📖
- Treatment directed at the tumor may also be contemplated (e.g., dexamethasone and perhaps even resective surgery).
radiation-induced vasogenic edema
- This may occur soon after treatment (typically ~1-14 days after therapy). However, edema can also occur in a more delayed fashion, within ~3 months after radiation.
- Symptoms vary depending on size and location of the treated area:
- Mild symptoms may include headache, fatigue, nausea.
- Rarely, edema may cause mass effect with compression of surrounding tissue. This may cause an exacerbation of pre-existing neurologic deficits that were caused by the tumor.
- Imaging:
- Contrast-enhanced MRI is the test of choice.
- White matter edema is seen, which generally doesn't enhance with contrast.
- Differential diagnosis: It may be difficult to sort out radiation-induced edema in the tumor bed (“pseudoprogression“) from true progression of the malignancy. This is especially challenging when radiation-induced edema occurs in a delayed fashion.
- Treatment for vasogenic edema that causes critical illness:
radiation necrosis
- Epidemiology:
- Radiation necrosis is a delayed complication which often occurs between ~6-18 months after therapy.(32601844) However, radiation necrosis may continue to occur even decades after therapy.(33273176)
- The risk may be highest with stereotactic radiosurgery (SRS) and lowest with whole brain radiotherapy (WBT). Chemotherapy, targeted therapy, or immunotherapy may also increase risk (e.g., BRAF inhibitors).(30072073; Odia 2022)
- Radiation necrosis tends to occur around the treatment target when managing brain tumors, but may also occur after treatment of tumors outside the brain (e.g., nasopharyngeal carcinoma).(30072073)
- Symptoms vary depending on the location of edema.
- Radiology:
- Treatment:
- Radiation necrosis is often self-limited with spontaneous improvement within ~6 months. Asymptomatic patients may be managed solely with observation.(30072073)
- Symptomatic patients may be managed with a moderate dose of steroid (e.g., 4-8 mg dexamethasone daily) until improvement occurs, followed by a gradual taper.(30072073) However, it's unclear whether steroid truly improves the eventual neurologic outcome, or whether it merely causes transient improvement.(28190444)
stroke-like migraine attacks after radiation therapy (SMART syndrome)
- SMART syndrome occurs months to decades after cranial irradiation. Symptoms may last for days to weeks, followed by resolution.(30072073)
- Clinical components may include:(Strowd 2022)
- (1) Stroke-like symptoms, with focal neurologic deficits. (Unlike stroke, deficits are transient and not associated with infarction on MRI.)
- (2) Migrainous symptoms (e.g., headache).
- (3) Seizures may be the most prominent finding.
- Imaging: MRI shows strictly unilateral increased T2 signal and gyriform enhancement within the radiation treatment field.
- Differential diagnostic considerations are listed below. Serial imaging may help sort this out (SMART syndrome may improve, whereas tumor recurrence will not).
- Tumor recurrence.
- Radiation necrosis.
- Other causes of gyriform enhancement are discussed here: 📖
- No treatment is necessary other than supportive care (including treatment of seizure as needed). Imaging and clinical findings regress spontaneously.
radiation-induced leukoencephalopathy
- This involves delayed brain injury that occurs in 5-30% of patients, months-years after treatment.(33273176)
- Imaging may show prominent T2/FLAIR hyperintensity in the periventricular and deep white matter.
- Clinically this may cause cognitive dysfunction, falls, and incontinence (which may mimic normal pressure hydrocephalus).(33273176)
radiation vasculopathy
- This may cause ischemic stroke in a third of patients who receive radiation to the brain, head, or neck.(33896532)
- Strokes often occur 3-5 years after treatment, in a subcortical location within the radiation field.(32596758)
Some notable associations are listed below, but this isn't exhaustive. This list doesn't include checkpoint inhibitors, which are discussed separately: 📖 (33896532; 33273176; 32487905, 34619783)
encephalopathy
- L-Asparaginase.
- 5-Azacytidine.
- Bortezomib.
- Capecitabine.
- Carmustine.
- Cisplatin.
- Cyclophosphamide.
- Cytosine arabinoside, aka cytarabine (IV or intrathecal). Intrathecal administration may cause a more severe necrotizing leukoencephalopathy.(33896532)
- Dacarbazine.
- Docetaxel.
- Doxorubicin.
- Etoposide.
- Fludarabine. May present with delayed and gradually worsening decline, 20-250 days after therapy. MRI may show leukoencephalopathy and diffusion restriction.
- 5-Fluorouracil.
- Gemcitabine.
- Hexamethylmelamine.
- Hydroxyurea.
- Iarotrecitinib.
- Ifosfamide. Occurs in ~10%, may be treated using intravenous methylene blue (50 mg IV q6-8hr) and thiamine (100 mg IV q4hr). (33896532, 31483060*)
- Imatinib.
- Interferons, interleukins.
- Iorlatinib.
- Levamisole.
- Methotrexate (IV or intrathecal).
- Combination of brain radiation plus methotrexate increases the risk of leukoencephalopathy.
- Differential diagnosis includes methotrexate-induced B12 deficiency.
- Misonidazole.
- Mitomycin C.
- Nelarabine.
- Paclitaxel. Occurs 1-3 weeks after treatment, may progress to coma.
- Pentostatin.
- Procarbazine.
- Suramin.
- Tamoxifen.
- Thalidomide.
- Thiotepa.
- Vinca alkaloids (e.g., vincristine).
seizure
- List of causative medications here.📖
acute cerebellar syndrome
- Capecitabine.
- Cyclosporine.
- Cytarabine (IV) – most common cause, especially at high doses.(32487905)
- 5-Fluorouracil.
- Hexamethylmelamine.
- Nelarabine.
- Oxaliplatin.
- Procarbazine.
- Vincristine.
aseptic meningitis
- Bortezomib (intrathecal).
- Cytarabine (intrathecal).
- Methotrexate (intrathecal).
- Trastuzumab (intrathecal).
acute myelopathy
- Cytarabine (intrathecal).
- Methotrexate (intrathecal).
PRES
- List of causative medications here: 📖
Malignancy and chemotherapy may increase the risk of nearly all CNS infections. The following may be particularly notable:
- Herpes simplex virus (HSV) encephalitis. 📖
- Varicella zoster virus (VZV). 📖
- Human herpesvirus 6 (HHV6). 📖
- JC virus, causing progressive multifocal leukoencephalopathy (PML). 📖
basics
- Patients with very high levels of immunoglobulins in their blood (usually due to B-cell malignancies) may develop hyperviscosity, leading to malperfusion and bleeding from obstructed capillaries.
- (Elevated cell counts may also technically cause high viscosity, but this is discussed in the section below on leukostasis.)
epidemiology
- Hyperviscosity syndrome occurs in ~20% of patients with Waldenstrom macroglobulinemia, and also in multiple myeloma (IgA > IgG). Hyperviscosity syndrome seems particularly related to IgM paraproteins, which are large and thus exert greater effects on viscosity.
- Anti-CD20 antibodies (rituximab, ofatumumab, obinutuzumab) can transiently increase IgM levels, thereby precipitating hyperviscosity syndrome. These agents should be held in patients whose viscosity is >3.5 centipoise, or if the IgM level is >4 g/dL.(31483060)
- Other diseases reported to cause hyperviscosity include Types 1 and 2 cryoglobulinemia, Sjogren syndrome, uncontrolled HIV, and high-titer rheumatoid factor.(30104220)
presentation
- Bleeding may occur in the skin and mucosa (e.g., bilateral epistaxis, gingival bleeding, or gastrointestinal bleeding). This may cause ongoing, refractory oozing that leads to recurrent presentations for epistaxis (before the underlying cause is recognized).
- Vision changes.
- Neurologic symptoms may include headache, vertigo, nystagmus, deafness, ataxia, delirium, intracranial hemorrhage, seizure, and coma.(31483060)
diagnosis
- Viscosity and/or immunoglobulin measurements generally take days to return. These studies are not needed to initiate therapy, if the index of suspicion is high and the clinical presentation is typical. Furthermore, clinical hyperviscosity syndrome may not always correlate well with serum viscosity (e.g., many patients may have elevated viscosity without clinical hyperviscosity syndrome).(30104220)
- Serum viscosity >4 centipoise (cP) is consistent with hyperviscosity syndrome. However, many laboratories won't have this test.
- The risk of hyperviscosity is related very roughly to the quantity of IgG, IgA, or IgM paraproteins. Hyperviscosity syndrome risk increases when IgM levels are >5 g/dL, IgA levels are >7 g/dL, or IgG levels are >10 g/dL.(31483060, 30104220) Alternatively, it is uncommon for hyperviscosity to occur with a paraprotein level <4 g/dL.(30104220) The “gamma gap” (total protein minus albumin, normally ~2.5 g/dL) may be used to roughly estimate the quantity of paraprotein, while awaiting precise quantification of immunoglobulin levels (paraprotein level may be very roughly estimated as total protein, minus albumin, minus 2.5 g/dL).
- Ophthalmoscopy demonstrating retinal hemorrhages or central retinal vein occlusion may support the diagnosis.(30104220)
treatment
- Plasmapheresis may gradually reduce the serum viscosity (by ~25% per session).
- Hematology/oncology consultants may help investigate and manage an underlying hematologic malignancy.
epidemiology
- Leukostasis occurs when very high levels of white blood cells increase blood viscosity, impairing perfusion. This usually occurs in blast crisis due to acute myeloid leukemia (AML) or chronic myeloid leukemia (CML). Myeloid blasts are larger than immature lymphocytes or mature granulocytes, causing the greatest risk of leukostasis.
- There is no accepted minimum leukocyte count for the diagnosis of leukostasis. However, leukostasis should be considered more strongly when the white blood cell count is >100,000/uL with >20% blasts.(30037446)
presentation
- Respiratory symptoms include dyspnea, cough, and hypoxemia (frequently requiring intubation).
- Chest X-ray may be normal, or may show an alveolar pattern of infiltrates.(27018197)
- CT scan may often show septal thickening, resembling interstitial edema. Other potential findings are nodules, focal airspace disease, and ground glass opacities.(Murray 2022)
- Neurological manifestations may include delirium, focal deficits, and seizure. Imaging findings are nonspecific (e.g., neuroimaging may show ischemic and hemorrhagic areas, edema, or masses).(27018197)
- Other features may include limb ischemia, priapism, renal failure, and renal vein thrombosis.(30037446)
evaluation
- Complete blood count with manual differential.
- Electrolytes, Ca/Mg/Phos, uric acid.
- ⚠️ Markedly elevated white blood cell count may cause pseudohyperkalemia. Measurement of potassium using a portable bedside blood gas analyzer may be more accurate. More on pseudohyperkalemia here: 📖
- INR, PTT, fibrinogen.
- Chest X-ray.
- Neuroimaging, as clinically indicated.
- Bone marrow biopsy by hematology is often needed.
treatment
- (1) Measures to reduce the white cell count:
- ⚠️ Leukostasis is a hematological emergency – hematology should be consulted immediately.
- Cytoreductive chemotherapy is the key intervention (often beginning with hydroxyurea, before precise identification of the leukemia type allows for more definitive chemotherapy).
- Leukapheresis is controversial, without proven benefit. Leukapheresis removes cells from the blood but doesn't remove proliferating blasts from the bone marrow, so patients with rapidly proliferating leukemias may have minimal and/or transient response. Furthermore, leukapheresis shouldn't be used for patients with acute promyelocytic leukemia, as this may trigger worsening coagulopathy.(31483060; 27018197)
- (2) Management/prophylaxis for tumor lysis syndrome (TLS).📖
- Spontaneous tumor lysis syndrome may occur in ~10% of patients with leukostasis, even before the initiation of chemotherapy.(30037446)
- The risk of tumor lysis syndrome following chemotherapy is high.
- (3) Management of disseminated intravascular coagulation, if present.
- Patients with definite or suspected acute promyelocytic leukemia (APL) should be started empirically on all-trans retinoic acid (ATRA): 📖.
- Thrombocytopenia may result from bone marrow infiltration and/or disseminated intravascular coagulation. Platelet transfusion may reduce the risk of intracranial hemorrhage (more on the management of thrombocytopenia here: 📖).
- (4) Aggressive investigation and treatment for infection.
- Despite elevated white blood cell count, patients may be neutropenic (either with a reduced absolute number of neutrophils, or “functional neutropenia” due to a lack of normal neutrophils).
- Early empiric initiation of antibiotics may be reasonable, if infection is suspected.(27018197)
- (5) Blood transfusion should be avoided if possible, as this may increase blood viscosity.
- (6) Volume resuscitation with crystalloid, for patients with hypovolemia.
- In truly hypovolemic patients, crystalloid administration will dilute the blood and thereby improve the viscosity.(30037446)
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- The main pitfall is failure to maintain a very broad differential diagnosis, with consideration for cancer-related diagnoses, treatment-related diagnoses, and diagnoses unrelated to malignancy.
Guide to emoji hyperlinks
- = Link to online calculator.
- = Link to Medscape monograph about a drug.
- = Link to IBCC section about a drug.
- = Link to IBCC section covering that topic.
- = Link to FOAMed site with related information.
- 📄 = Link to open-access journal article.
- = Link to supplemental media.
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