Mechlorethamine is the original nitrogen mustard, which inhibits DNA and RNA syntheses by producing interstrand and intrastrand cross-links in DNA. It is used in lymphomas and malignant effusions. When used at conventional intravenous (IV) doses, mechlorethamine does not cause neurotoxicity. When used in high-dose IV regimens, such as preparation for bone marrow transplantation (BMT), the drug has been reported to cause encephalopathy , headache, and seizures [1, 2]. The symptom onset is usually within a few days of treatment; spontaneous recovery is typical. Mechlorethamine has also been administered during intra-arterial (IA) chemotherapy for treatment of recurrent gliomas in the 1950s and 1960s, but was associated with significant cerebral edema, seizure activity, focal neurological deficits, and encephalopathy [3].

Chlorambucil is an orally administered nitrogen mustard interfering with DNA replication and RNA transcription by cross-linking DNA strands, used in the treatment of chronic lymphocytic leukemia (CLL), Hodgkin’s lymphoma, and non-Hodgkin’s lymphomas. Rarely, seizures may occur. A history of nephrotic syndrome and high-dose chlorambucil pulses are risk factors for chlorambucil-induced seizures [4, 5]. Ocular toxicities including retinal edema and hemorrhage, as well as keratitis, have been described [6]. Uncommon central neurotoxicities include agitation, ataxia, confusion, drug fever, hallucinations, encephalopathy, and myoclonus [7, 8]. PNS toxicity of chlorambucil includes neuropathy, tremor, and myoclonia [9, 10].

Cyclophosphamide is a prodrug that requires activation in the liver. Antineoplastic properties are derived from cross-linking DNA strands and decreasing DNA synthesis. It is frequently used in combination chemotherapy regimens for many solid and hematologic tumors. Neurotoxicity is uncommon, especially compared to ifosfamide, but may present during high-dose IV infusions used for hematopoietic stem cell transplant. Toxicity at these doses includes a mild, reversible encephalopathy with dizziness, blurred vision, and confusion. Posterior reversible encephalopathy has also been described [11].

Ifosfamide is an alkylating agent structurally similar to cyclophosphamide that is used for treatment of many solid and hematopoietic tumors, known to frequently cause CNS toxicity. Central neurotoxicity occurs in 10–30% of all patients that receive high-dose IV ifosfamide treatment [12–15]. The toxicity is more likely to occur when IV therapy is continuous over several days or given in a large bolus dose, as opposed to fractionated schedules. Other risk factors include low serum albumin [12, 13], renal dysfunction [12, 13], use of the antiemetic aprepitant [16–19], underlying brain disease [20], concurrent phenobarbital treatment [21], previous neurotoxicity with ifosfamide [12], and prior cisplatin therapy [12, 13]. Accumulation of chloroacetaldehyde, a metabolite of ifosfamide, is thought to cause the encephalopathy. Neurotoxicity can occur hours to days into the treatment and the majority of patients do not require treatment; the encephalopathy resolves completely within days [22]. Small studies have used dexmedetomidine, thiamine, and/or methylene blue as treatment of prevention of ifosfamide-induced encephalopathy [23–26]. The most common symptoms include delirium, mutism, visual hallucinations, seizures, focal motor deficits, facial nerve palsy, and aphasia. Cases of death [27, 28] and irreversible neurologic deficits have been reported [22]. Electroencephalography (EEG) generally reveals diffuse, slow-wave activity, without epileptiform discharges. Other neurotoxicity with ifosfamide is typically described in the setting of encephalopathy but includes seizures [29, 30], ataxia [29], neuropathy [31], extrapyramidal symptoms [32, 33], and cranial nerve dysfunction [13].

Melphalan inhibits DNA and RNA syntheses by creating cross-links in DNA. It is used in multiple myeloma, ovarian cancer, and as a conditioning regimen for autologous hematopoietic stem cell transplantation. Neurotoxicity is uncommon, although cases of encephalopathy and seizures have been reported [34–36].

Bendamustine is a nitrogen mustard derivative that causes single- and double-strand breaks leading to cell death. It is used in the treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma. Neurotoxicity is uncommon with fatigue, headache, vertigo, anxiety, and depression described [37, 38].

Estramustine , a nitrogen mustard linked to estradiol, has both antiandrogen and anti-microtubular effects. It is mainly used for refractory prostate cancer and is not associated with significant CNS toxicity. Trials report uncommon neurotoxicity such as lethargy, insomnia, emotional lability, anxiety, and headache [39]. Approximately 25% of patients experienced a thromboembolic event [40]. Rare cases of thrombotic microangiopathy with cerebral infarction have been described [41].

Busulfan is a non-cell-cycle-specific alkylating agent that interferes with DNA replication and transcription of RNA. It is used as an oral treatment for chronic myelogenous leukemia (CML) and IV in hematopoietic stem cell transplant conditioning regimens. Busulfan is known to cross the BBB easily with a CSF-to-plasma ration of 1:1. Seizures have been reported with IV busulfan and with high-dose oral busulfan [45–47]. The seizures usually appear within 48 h of drug administration. Seizures are more common in adults compared to children [48]. When busulfan is used as a conditioning regimen for transplant, prophylactic anticonvulsant therapy should be initiated (e.g., phenytoin, levetiracetam, benzodiazepines, or valproic acid) prior to treatment. It should be noted that phenytoin increases busulfan clearance by greater than 15% and doses should be adjusted accordingly. Busulfan should be used with caution in patients predisposed to seizures, history of seizures, head trauma, or with other medications associated with inducing seizures. Dimethylacetamide is the solvent in IV busulfan and has been associated with hallucinations, somnolence, lethargy, and confusion. Other neurotoxic side effects of busulfan include insomnia, fever, anxiety, headache, chills, vertigo, depression, confusion, delirium, encephalopathy, and cerebral hemorrhage [49].

Dacarbazine causes DNA double-strand breaks leading to cell apoptosis. It is commonly used in Hodgkin’s lymphoma, melanoma, and many sarcoma histologies. Seizures, encephalopathy, and dementia have rarely been reported [50]. Mild neurotoxicy, such as headache and fatigue, are more common and self-limiting.

Temozolomide is a prodrug that is converted to the active alkylating metabolite MTIC. It is used in the treatment of Ewing’s sarcoma, melanoma, and many types of brain tumors including astrocytoma and glioblastoma. Central neurotoxicity appears to be very uncommon, with reports of seizures and exacerbation of focal neurological deficits [51]. However, it is difficult to differentiate if these symptoms might be related to the underlying brain tumor, the medication, or a combination of both. Transient neurological deterioration may occur in the early stages of therapy in glioma patients and has been referred to as “tumor flare” syndrome, “treatment effect,” and tumor “pseudoprogression” [52, 53]. The incidence of tumor “pseudoprogression” ranges from 28 to 66% in glioblastoma patients and typically occurs within 3 months post-completion of temozolomide and concurrent radiation [53]. Neuroimaging shows an increased area of contrast enhancement and enlargement of noncontrast T2/FLAIR hyperintensities surrounding the enhancement. Treatment of “pseudoprogression” may include corticosteroids, bevacizumab, or watchful waiting with short-interval brain MRI depending on the extent radiological changes and neurological symptoms.

Thiotepa is an alkylating agent that produces DNA cross-links leading to inhibition of DNA, RNA, and protein syntheses. It is used for ovarian cancer, intracavitary effusions, intrathecally for leptomeningeal metastases, intravesically for bladder cancer, and at high doses for hematopoietic stem cell transplant in patients with active CNS malignancy. It readily crosses the BBB [54]. Thiotepa may cause chills, vertigo, fatigue, fever, and headache. Intrathecal use can cause similar toxicity to that of MTX and Ara-C including a mild, reversible aseptic meningitis and, in rare cases, a transient or persistent myelopathy [55–57]. Neurotoxicity from thiotepa is significantly increased in patients with previous CNS radiation [58]. CNS toxicity is rare at conventional IV doses. High doses of thiotepa IV have been associated with neurotoxicity in the form of encephalopathy, including fatal encephalopathy [59].

Hexamethylmelamine structurally resembles an alkylating agent but has demonstrated activity in tumors resistant to classic alkylating agents. Its mechanism is not fully understood, but it is thought to bind and damage DNA. It is used for recurrent ovarian cancer [60]. The parent drug does not readily cross the BBB, but the metabolites readily enter the CNS. Peripheral neuropathy with hexamethylmelamine can occur, but the drug has been administered safely to patients with pre-existing neuropathy due to cisplatin [61, 62]. It is recommended that a neurological examination be done routinely before each cycle and throughout treatment. The most common neurotoxic side effects include headache and mild encephalopathy. Less frequent CNS toxicities include seizures, ataxia, tremor, and Parkinsonism. These usually occur in patients receiving high-dose daily treatment, and in most cases are reversible after drug discontinuation [59].

Cisplatin inhibits DNA synthesis by the formation of DNA cross-links. It is utilized in a variety of oncologic and hematologic malignancies. Cisplatin has a wide range of neurotoxicity including peripheral neuropathy, ototoxicity, vestibulopathy, and encephalopathy.

The peripheral neuropathy associated with cisplatin is a sensory peripheral neuropathy. This typically begins developing at a cumulative dose of 300 mg/m². Once a cumulative dose of 500–600 mg/m² has been achieved, almost all patients have evidence ofperipheral neuropathy [63–65]. Increasing the dose intensity of cisplatin therapy has been shown not to increase the severity of the peripheral neuropathy [66]. There is significant variance among patients in the susceptibility of peripheral neuropathy [64, 67, 68], thought to be due to genetic polymorphisms in the enzymes responsible for cisplatin metabolism [69, 70].

Cisplatin-induced peripheral neuropathy is an axonal neuropathy that affects large myelinated sensory fibers [63, 67, 71, 72]. The major site of damage is the dorsal root ganglion [73], where cisplatin promotes alterations in cell-cycle kinetics leading to induction of apoptosis [74]. Oxidative stress and mitochondrial dysfunction may also trigger neuronal apoptosis and could also play a role in cisplatin-induced peripheral neuropathy [75–77].

Symptomatology of cisplatin-induced peripheral neuropathy includes numbness, paresthesias, and pain. Normally these symptoms begin bilaterally in the toes and fingers, spreading proximally to the arms and legs. Pinprick, temperature sensation, and motor strength are usually intact or less severely affected compared to proprioception and reflexes [63]. Nerve conduction studies exhibit sensory axonal damage, with decreased amplitude of sensory nerve action potentials and prolonged sensory latencies [78].

After discontinuation, cisplatin-induced peripheral neuropathy worsens in 30% of patients [71, 72], and symptoms may even begin after therapy is discontinued. A large study in patients with testicular cancer found that peripheral neuropathy remained detectable on long-term follow-up (i.e., greater than 5 years) in approximately 20% of patients, and caused significant symptoms in 10% of patients [65]. Once developed, there is no effective therapy to reverse the neuropathy and treatment is aimed at controlling symptoms. Over time, the peripheral neuropathy improves but full recovery is often not observed.

High-frequency sensorineural hearing loss with tinnitus is a dose-dependent toxicity of cisplatin [79]. This has been reported with both intravenous and rarely with intraperitoneal use [80]. Cisplatin-induced ototoxicity occurs from damage to the outer hair cells in the organ of Corti and the vascularized epithelium in the lateral wall of the cochlea [81, 82]. Ototoxicity occurs in approximately 15–20% of patients receiving cisplatin, and early detection with audiometry is vital to prevention as there is no consensus on pharmacologic agents to prevent or treat this toxicity.

The most frequent neurotoxic side effects of cisplatin involve the peripheral nervous system . However, central nervous system toxicity can also be very significant in selected patients, and will depend on the dose and route of administration (i.e., IV vs. IA). Seizures and diffuse encephalopathy are the most common forms of CNS toxicity associated with cisplatin [83–85], yet still rarely occur (Fig. 15.1a, b). This occurs due to acute injury to neural tissues, metabolic abnormalities, or a combination of both. Hypomagnesaemia is common in patients receiving cisplatin, noted in 55–60% of patients. It is caused by impaired magnesium reabsorption in the proximal renal tubules [86]. Both seizure activity and encephalopathy can occur in the setting of hypomagnesaemia, along with diffuse muscle weakness, depending on the severity of the magnesium deficit. Patients are also at risk for hyponatremia, which can result from the syndrome of inappropriate antidiuretic hormone (SIADH) , excessive hydration with hypotonic fluids during cisplatin infusion, or severe cisplatin-induced emesis [87]. In rare cases, especially those with intracranial space-occupying lesions, excessive hydration during cisplatin therapy can result in cerebral edema, somnolence, seizure activity, and tonsillar herniation [88]. Lhermitte’s phenomenon , manifesting as paresthesias in the back and extremities with neck flexion can be seen in patients receiving cisplatin. This is most likely caused from transient demyelination of the posterior columns [89]. Lhermitte’s phenomenon is self-limiting after drug discontinuation [90, 91]. Encephalopathy may occur as a direct toxic effect during IV treatment, but is even more common during IA infusion [3, 92]. Other symptoms that can arise during or within hours to days of IV cisplatin include stroke, seizures, cortical blindness, retinal toxicity, dysphasia, and focal motor deficits. The neurological injury usually resolves without specific intervention and may not recur with subsequent cycles of cisplatin. In patients with stroke, angiography may reveal branch occlusion or, in some cases, be completely normal. The cause of cisplatin-induced stroke remains unclear; possible mechanisms include vasospasm in the setting of hypomagnesaemia, coagulopathy, and drug-induced endothelial injury.

Intra-arterial cisplatin is associated with a broad range of CNS neurological complications, including encephalopathy, confusional states, seizures, stroke, chronic leukoencephalopathy, and ocular toxicity [3, 92]. The ocular injury can manifest as optic neuropathy and/or retinopathy, and may include retinal infarcts. The risk for ocular toxicity is reduced if the catheter is advanced beyond the origin of the ophthalmic artery. However, supra-ophthalmic delivery of cisplatin has been associated with more frequent and severe neurological toxicity.

Carboplatin is a platinum alkylating agent that covalently binds to DNA-producing interstrand DNA cross-links. It is used in many different solid and hematologic malignancies, as well as in high doses for hematopoietic stem cell transplant. Peripheral neuropathy and CNS toxicity are uncommon when carboplatin is given at conventional dosing. A severe neuropathy can develop with higher than standard dose carboplatin, in the setting of hematopoietic cell transplantation [93]. Reversible posterior leukoencephalopathy has been described with carboplatin [94] and retinal toxicity after IA administration [95], along with stroke-like symptoms [96] and cortical blindness [97]. The incidence of neuropathy is lower than with cisplatin [98]. Carboplatin, via the IA route, has been used for the treatment of primary or metastatic brain tumors and appears to have less neurotoxicity compared to cisplatin [3].

Oxaliplatin forms cross-links in DNA leading to inhibition of DNA replication and transcription. It is commonly used in colorectal cancer, gastric cancer, esophageal cancer, pancreatic cancer, and types of lymphomas. Peripheral neuropathy is common with oxaliplatin and comprises two distinct syndromes. The first is an acute peripheral neurotoxicity that can appear during or shortly after the first couple of infusions. The second is a cumulative sensory neuropathy, with distal loss of sensation and dysesthesias. Oxaliplatin-induced peripheral neuropathy is extremely common with greater than 85% of patients affected [99].

Acute symptoms are more frequently observed at single doses ≥130 mg/m² than with doses ≤85 mg/m² [100]. Typical symptoms include cold intolerance with discomfort swallowing cold beverages, throat discomfort, sensitivity to touching cold items, paresthesias and dysesthesias of the hands, feet, and perioral region, and muscle cramps. Prolonging the infusion time from 2 to 6 h decreases the incidence of acute neuropathy including pseudolaryngospasm [101].

General consensus has been that oxaliplatin-induced acute neuropathy resolves after two to three days; a more recent report suggests that it may not completely resolve between oxaliplatin doses with every two-week dosing [102]. Symptoms are typically most severe with the first cycle but recur with each cycle. In subsequent cycles, the severity of the acute neuropathy is approximately half as severe compared to the first cycle and maintains that severity throughout treatment [102].

The mechanism of oxaliplatin-induced acute peripheral neuropathy has been postulated to be a result of chelation of calcium by oxalate, a metabolite of oxaliplatin. This causes a transient activation of disinhibited peripheral nerve voltage-gated calcium-dependent sodium channels, causing hyperexcitability of peripheral nerves [103, 104]. As patients progress through therapy, acute changes in axonal excitability seem to become less pronounced. This is likely due to chronic nerve dysfunction and sensory loss that mask the acute effects at higher cumulative doses [105]. Calcium and magnesium supplementations for treatment and prevention are controversial. Several studies have shown benefit [106–108] while others, including a prospective phase III study, were not able to show benefit [109, 110].

The second distinct oxaliplatin-induced peripheral neuropathy is a cumulative sensory neuropathy. It is dose-limiting with a late onset comparable to that of cisplatin. It presents as a symmetric distal axonal neuropathy without motor involvement, and with rare autonomic involvement. The mechanism of this neuropathy is similar to cisplatin. Oxaliplatin forms fewer platinum-DNA adducts compared to cisplatin, and thus is slightly less neurotoxic [111]. Other rare manifestations of neurotoxicity include urinary retention and Lhermitte’s phenomenon in patients receiving high cumulative oxaliplatin doses [112, 113]. Reversible posterior leukoencephalopathy has also been reported [114–116].

Procarbazine is a prodrug that is activated in the liver. It inhibits transmethylation of methionine into transfer RNA and thus inhibits DNA, RNA, and protein syntheses. It penetrates the BBB and is used for the treatment of lymphomas and brain tumors. Procarbazine can cause a mild reversible encephalopathy at normal doses (100 mg/m² for 14 days every 28 days). At this dose it may also rarely cause psychosis and stupor [117]. The incidence of encephalopathy may be higher in patients receiving higher doses for gliomas [118]. In addition, due to its weak activity as an MAO inhibitor, procarbazine can cause hypertensive encephalopathy, headache, and delirium when administered in combination with sympathomimetic agents or after consumption of tyramine-containing foods.

After IT administration, MTX induces a chemical meningitis in approximately 10% of patients [189, 190]. Symptoms include headache, stiff neck, photophobia, and low-grade fever, arising within hours of drug administration and potentially lasting for days. CSF analysis will typically demonstrate a mild pleocytosis, with no evidence of a viral and/or bacterial process. The reaction appears to be idiosyncratic, does not usually recur with subsequent cycles of IT treatment, and does not seem to be dose-related. Oral corticosteroids or hydrocortisone along with the MTX may decrease the severity and incidence of chemical meningitis. The symptoms are usually self-limiting and require no treatment. Patients that have had an acute reaction to IT MTX do not appear to be predisposed to developing a late or chronic effect of the drug.

Less common acute and subacute side effects of IT and systemic MTX include seizures, encephalopathy, transient focal neurologic deficits, and transverse myelopathy [189, 190]. Seizures rarely occur as an acute toxicity after IT administration and are self-limiting. The most extensive experience with this complication has been in pediatric patients receiving IT MTX for treatment of acute leukemia [191]. Acute and subacute encephalopathy can occur in the setting of high-dose IV MTX (3–12.5 g/m²; 2.5–15% of patients), most often administered in combination with other chemotherapy agents for CNS lymphoma [188]. The clinical presentation typically includes somnolence, the acute onset of focal signs such as hemiparesis, dysphasia, dysarthria, and occasional seizure activity. Brain CT and MRI may demonstrate transient white matter abnormalities, or can be normal in some cases (Fig. 15.4). One report discussed the use of MRI within 1 h of onset of the syndrome. This revealed bilateral, symmetrical restricted diffusion involving white matter of the cerebral hemispheres, without evidence of vasospasm or perfusion defect [192]. The authors suggested that transient cytotoxic edema in the white matter was the likely mechanism of MTX-induced neurotoxicity. EEG evaluation usually reveals an abnormal study, with diffuse slowing of the background. The syndrome is not likely to correlate with serum or CSF MTX concentrations, and symptoms can occasionally recur with subsequent courses of treatment. In most cases, there is complete resolution of the clinical and imaging abnormalities but, rarely, a chronic leukoencephalopathy can be noted. Transverse myelopathy can occur after IT MTX, often within hours to weeks of administration of the drug [190, 193]. In most cases, the toxicity develops after the patient has received multiple doses of MTX. The clinical examination reveals bilateral leg weakness, pain, spasticity, sensory loss, bladder dysfunction, and gait difficulty. MRI of the spinal cord may be normal or show T2 high signal abnormalities with patchy enhancement [194]. Pathological examination is often unrevealing, although one case has been reported with vacuolar degeneration and necrosis, without inflammation [195]. The symptoms improve after drug discontinuation but the extent of improvement is variable [196]. Accidental overdosage of IT MTX is extremely uncommon, with cases describing no neurologic injury [197] and others reporting severe reactions to overdosage, with rapidly progressive encephalopathy and death [198]. Potential treatment options for patients with an overdose of IT MTX include CSF drainage, ventriculo-lumbar perfusion, and administration of IT carboxypeptidase-G2, an enzyme that hydrolyzes MTX into inactive metabolites [199, 200].

Chronic and/or late side effects of IT and IV MTX occur at least six months after initial drug administration [189, 190]. The most common chronic effect is a leukoencephalopathy, which is well described in children with acute leukemia, but can also occur in adults [201]. In children, the clinical presentation includes progressive learning disorders, developmental delay, memory loss, gait difficulty, and urinary incontinence. These symptoms are similar in adults, with confusion and memory loss that often progresses to dementia, as well as somnolence, irritability, impaired vision, dysphasia, seizures, and ataxia. Imaging with CT and MR reveals diffuse white matter damage, cortical atrophy, ventricular enlargement, and punctate areas of calcification within the basal ganglia and deep white matter (Fig. 15.5). In addition, asymptomatic patients who have only received high-dose IV or IT MTX may demonstrate similar, but much milder, damage to the white matter on imaging studies.

The leukoencephalopathy is most likely to occur after combination treatment with high-dose IV MTX, IT MTX, and cranial irradiation (45%), with a much lower incidence following high-dose MTX and/or IT MTX alone (2% or less) [190, 202]. Neurotoxicity is especially enhanced when the patient receives irradiation before the administration of MTX (Fig. 15.6). The mechanisms underlying this synergistic toxicity remain unclear. It may be due to a radiation-induced increase in the permeability of the BBB, reduced clearance of MTX from the CSF, increased passage of MTX into the white matter through the ependymal–brain barrier, and potential direct cellular toxicity caused by irradiation [190]. Neuropathological changes are most notable around the periventricular white matter and deep centrum semiovale, and include demyelination, multifocal white matter necrosis, astrocytosis, dystrophic calcification of deep cerebral vessels, and axonal damage. Inflammatory cellular infiltration is typically not present.

Doxorubicin and daunorubicin are anthracycline antibiotics that bind nucleic acids, disrupting the structural integrity of DNA, and are used for the treatment of numerous hematologic and solid malignancies. Following IV infusion, neither drug penetrates the BBB to any significant degree; central neurotoxicity has not been reported. Doxorubicin when administered with cyclosporine has resulted in neurological symptoms and coma [219]. However, when administered IA for brain tumors, doxorubicin has been linked to cerebral infarcts and hemorrhagic necrosis [220]. Inadvertent IT injection of either drug can lead to an acute or subacute ascending myelopathy and encephalopathy, which can be fatal [221].

Epirubicin is an anthracycline known to inhibit DNA and RNA syntheses by intercalating between DNA base pairs used in breast cancer, gastric cancer, and types of sarcoma. Neurotoxicity is rare though studies have reported lethargy and fever.

Idarubicin is mainly used in the treatment of acute myeloid leukemia (AML) . Like other anthracyclines, it inhibits DNA and RNA syntheses by intercalation between DNA base pairs. Neurotoxicity is rare with headache and seizure described. All anthracyclines can cause arrhythmias and cardiomyopathies that can lead to cerebrovascular complications.

Dactinomycin is used in testicular cancer, gestational trophoblastic neoplasm, and several types of sarcomas. It intercalates DNA inhibiting DNA, RNA, and protein syntheses. Neurotoxicity is rare including fatigue, lethargy, and malaise [222, 223].

Bleomycin acts by directly binding to DNA, leading to both single- and double-strand breaks, as well as inhibiting RNA and protein synthesis. Bleomycin is utilized in the treatment of testicular cancer, and Hodgkin’s lymphoma. Generally, neurotoxicity is uncommon. An idiosyncratic reaction has been reported in 1% of lymphoma patients treated with bleomycin that is similar to anaphylaxis, but can include symptoms of confusion, fever, and chills along with other non-CNS toxicity. Cerebral infarction has been described following the combination of bleomycin and cisplatin [224].

Mitomycin acts as an alkylating agent by producing DNA cross-links and therefore inhibiting DNA and RNA syntheses. It is used for gastric and pancreatic cancer. It is only known to cause central neurotoxicity in the context of mitomycin-induced disseminated intravascular coagulation and thrombotic microangiopathy, which can lead to headaches and other CNS complications [225].

Mitoxantrone has a mechanism similar to anthracyclines by intercalating into DNA, resulting in cross-links and strand breaks. It is utilized in the treatment of acute myeloid leukemia (AML) and multiple sclerosis. Like anthracyclines, neurotoxicity is uncommon with headache, anxiety, depression, and seizures reported [226]. Radiculopathy and myelopathy have been reported following intrathecal administration [227].

Topotecan is a topoisomerase I inhibitor and derives its activity from binding to topoisomerase I and stabilizing the cleavable complex so that relegation of the cleaved DNA strand cannot occur. It is used in cervical, ovarian, small cell lung cancer, and sarcoma. Neurotoxicity is rare with fatigue and headache reported [228, 229].

Irinotecan is a topoisomerase I inhibitor resulting in the prevention of re-ligation of single-strand breaks in DNA during DNA synthesis. It is used in colon, lung, cervical, ovarian, pancreatic, glioblastoma, and skin cancer. Irinotecan has been associated with nonspecific dizziness and insomnia, as well as occasional episodes of dysarthria, either alone or in combination with other drugs. The dysarthria resolves after discontinuation of the drug.

Etoposide, a topoisomerase II inhibitor, delays transit of cells through the S phase and arrests cells in late S or early G2 phase, halting the cell cycle and leading to apoptosis. Etoposide is commonly used in lung cancer, testicular cancer, hematopoietic stem cell transplant, and mobilization. Neurotoxicity is uncommon, with rare reports of peripheral neuropathy, transient cortical blindness, and optic neuritis. Hypersensitivity reactions can occur during the infusion that can manifest with chills, fever, and loss of consciousness. It is important to note that the injectable formulation contains ethanol (approximately 33% v/v) and may contribute to neurotoxicity due to ethanol toxicity, especially at higher doses used for stem cell mobilization. Rarely, confusion, papilledema, somnolence, worsening motor deficits, and seizures have been described [230].

Teniposide (VM-26) is a topoisomerase II inhibitor that induces single- and double-strand breaks in DNA and DNA–protein cross-links. Teniposide is used in refractory acute lymphoblastic leukemia (ALL). It is highly protein bound and poorly penetrates the BBB. Hypersensitivity reactions can occur and include chills and fever. Acute CNS depression has been reported with high IV dosing [231]. Like in etoposide, there is an ethanol component to the diluent used in the medication, which can cause acute ethanol toxicity leading to CNS depression.