The symptoms of brain injury from exposure to hazards like lead paint and toxic chemicals vary widely. Chemotherapy-induced peripheral neurotoxicity is probably an underestimated clinical problem in cancer survivors. Elderly patients with primary CNS lymphoma should be informed about these risks; it should also be considered by the treating oncologists whether these patients can be treated with reduced-dose WBRT or avoid WBRT altogether after-high dose methotrexate. For instance, in the period from 1950 to 2010, overall cancer-related mortality adjusted for age decreased in the United States by more than two-thirds in young patients (i.e., younger than age 14), by more than 50% in patients through age 44, and by at least 25% through age 64.1. Recent studies report a desire among patients for better information and support related to long-term/persistent treatment-related toxicities as well as greater awareness of these side effects among health care providers.53. Among several cancer treatment–related side effects, neurotoxicity can be particularly severe and long lasting and can affect the quality of life (QoL) as well as the daily life activities of cancer survivors.2,3 The peculiar characteristics and biology of neurons (e.g., high specialization, selective metabolism, incapacity to replicate) and the very limited possibility of the central nervous system (CNS) to effectively recover from severe and extensive damage make CNS neurotoxicity a well-known, critical medical problem. 1. MRI shows patchy abnormalities within the white matter that enhance with gadolinium. Myelin basic protein levels in the CSF may be elevated.24 Typically, only half of those affected will show any sign of recovery. The DRG are the main target of platinum drugs.11 These drugs cause intrastrand adduct and interstrand crosslink formation with a subsequent alteration of the tertiary structure of the DNA in DRG neurons. Moreover, because cancer-targeted therapies frequently are used after or in combination with conventional chemotherapy, the possibility that their use could worsen the toxicity profile of standard neurotoxic chemotherapy drugs also should be considered. The central nervous system has a limited capacity to recover from injuries, and it is not surprising that severe damage can determine long-term or permanent neurologic dysfunction. Apart from dose reduction or discontinuing the drugs implicated in the development of neurotoxicity, there is very little in the way of specific pharmacological management to reverse their side effects. However, the most recent cancer-targeted drugs also are not completely safe.6 The peripheral neurotoxicity of both conventional and targeted compounds will be treated separately. On the clinical side, a very important contribution to better knowledge of cancer treatment–related neurotoxicity could come from a more homogeneous, reliable, and systematic collection of the clinical data of treated patients. Identifying signs and symptoms of cancer treatment-related neurotoxicity is a critical piece of every oncology nurse’s role. A subacute form of leukoencephalopathy occurs in approximately 2% of patients receiving 5-FU in combination with levamisole (an immunomodulatory agent). Despite these challenges, the proper design of a reliable assessment plan is now easier for patients with CIPN. Long-term effects of chemo on the cognitive function of cancer patients, Chemotherapy-induced neuropathy: a comprehensive survey, Chemotherapy-induced peripheral neurotoxicity (CIPN): an update, Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics, Chemotherapy-induced peripheral neurotoxicity, Physician-assessed and patient-reported outcome measures in chemotherapy-induced sensory peripheral neurotoxicity: two sides of the same coin, Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle, Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2, Neuronal drug transporters in platinum drugs-induced peripheral neurotoxicity, Mechanisms underlying chemotherapy-induced neurotoxicity and the potential for neuroprotective strategies, Morphological and morphometric analysis of paclitaxel and docetaxel-induced peripheral neuropathy in rats, Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells, Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl-l-carnitine: effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells, Damage to the cytoskeleton of large diameter sensory neurons and myelinated axons in vincristine-induced painful peripheral neuropathy in the rat, Bortezomib-induced painful peripheral neuropathy: an electrophysiological, behavioral, morphological and mechanistic study in the mouse, Bortezomib-induced painful neuropathy in rats: a behavioral, neurophysiological and pathological study in rats, Bortezomib induces the formation of nuclear poly(A) RNA granules enriched in Sam68 and PABPN1 in sensory ganglia neurons, Preclinical and clinical development of the proteasome inhibitor bortezomib in cancer treatment, Proteasome inhibitors increase tubulin polymerization and stabilization in tissue culture cells: a possible mechanism contributing to peripheral neuropathy and cellular toxicity following proteasome inhibition, Evaluation of tubulin polymerization and chronic inhibition of proteasome as citotoxicity mechanisms in bortezomib-induced peripheral neuropathy, Thalidomide sensory neurotoxicity: a clinical and neurophysiologic study, Lenalidomide in patients with chemotherapy-induced polyneuropathy and relapsed or refractory multiple myeloma: results from a single-centre prospective study, Interventions for preventing neuropathy caused by cisplatin and related compounds, Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline, Neurological complications following alemtuzumab-based reduced-intensity allogeneic transplantation, Guillain-Barré syndrome after use of alemtuzumab (Campath) in a patient with T-cell prolymphocytic leukemia: a case report and review of the literature, A phase I weekly dosing study of brentuximab vedotin in patients with relapsed/refractory CD30-positive hematologic malignancies, Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma, Severe peripheral motor neuropathy in a patient with Hodgkin lymphoma treated with brentuximab vedotin, Long-term neuropathy after oxaliplatin treatment: challenging the dictum of reversibility, Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer, Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer, Chemotherapy-induced neuropathy and its association with quality of life among 2- to 11-year colorectal cancer survivors: results from the population-based PROFILES registry, Peripheral neuropathy in colorectal cancer survivors: the influence of oxaliplatin administration. Guido Cavaletti. ASCO Connection Symptoms range from mild to severe. Generally, symptoms are self-limiting, but in some patients the symptoms persist. Patients most at risk are those with impaired renal function, low serum albumin, pelvic tumors, and previous exposure to cisplatin.88 The risk of encephalopathy varies with route of administration. The diagnosis of drug-induced encephalopathy is typically one of exclusion. (May 14, 2015) Honoraria: None. In most cases, CIPN ensuing after conventional treatments consists of dose-dependent, predominantly sensory, length-dependent neuropathies/neuronopathies. The neuropathy tends to be predominantly sensory in nature, with a glove and stocking distribution. 5-fluorouracil (5-FU), a pyrimidine analogue, is widely used in the treatment of gastrointestinal malignancies; it is administered either as a short intravenous bolus or as a prolonged continuous infusion. Neurotoxicity is not that simple. 40% of patients receiving chemotherapy and depends on the type of cytotoxic drug, the duration of administration, cumulative dose and pre-existing peripheral neuropathy.2-7 Symptoms are predominantly sensory, but the neurotoxicity also appears as a sensory-motor neuropathy and occasionally it will be accompanied by dysfunction of Its neurotoxicity is thought to stem from widespread disruption of various metabolic pathways in the brain and can be acute or chronic. Also, the pathogenesis of cancer-targeted drugs effects on the PNS is largely unknown. Symptoms such as sensory ataxia, pain, and severe numbness can be disabling, and interfere with functional ability and quality of life. Improvement in surgery and the use of multimodal therapies in patients with ovarian cancer has allowed clinicians to achieve a 5-year survival rate of greater than 40% in this population.43 In a study performed with a cohort of 116 patients with ovarian cancer, investigated at a median of 501 days after the end of treatment, 62% of the 100 responders reported the presence of peripheral neuropathy (according to EORTC questionnaires), and 29% defined them as significant intensity.44. Patients most at risk are children, those who have received previous cranial radiotherapy, or those receiving concomitant intravenous and intrathecal therapy. Platinum-induced peripheral neurotoxicity (PIPN) is a common side effect of platinum-based chemotherapy that may cause dose reduction and discontinuation, with oxaliplatin being more neurotoxic. Neurotoxicity is rare, but may include acute cerebellar dysfunction in 3% to 7% of patients, causing gait ataxia, nystagmus, and scanning speech. Cancer patients have frequently recognized decreased cognitive function (“chemo-brain”) during chemotherapy, which, in the past, was attributed by their physicians to stress or depression. Neurotoxic side effects of chemotherapy occur frequently and are often a reason to limit the dose of chemotherapy. Abstract. Relationships marked “L” indicate leadership positions. Cognitive effects of cancer and its treatments at the intersection of aging: what do we know; what do we need to know? Finally, the long-term course and reversibility of symptoms and signs have very rarely been investigated so far.4–9. Paola Alberti. Currently there are few therapies able to prevent neurological toxicity preemptively. published online before print Mols et al performed a systematic review of the available literature and found 11 studies that assessed the relationship that exists between CIPN and QoL.45 Eight of these studies reported an association, whereas three failed to observe any association between CIPN and QoL. EEG is particularly helpful if seizures occur, and will typically show generalized slowing with delta wave activity.7 Encephalopathy due to cytotoxic drug exposure is generally self-limiting and recovers spontaneously. Cerebellar signs in an oncology patient are usually due to direct spread of cancer, particularly if it is asymmetric. The ASCO Post In Table 2, examples regarding the possible peripheral neurotoxic effect of cancer-targeted drugs are reported. Research Funding: Paola Marmiroli, Merck Serono (I). Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common, potentially severe and dose-limiting adverse effect of cancer treatment; however, the effects of CIPN on the daily life of individuals are not completely understood. It may cause cerebrovascular accidents during the first few weeks of its administration. Acute neurotoxicity symptoms, most commonly cold-induced paraesthesiae and jaw or throat tightness, were reported by all patients treated with oxaliplatin (n = 22) and none of those treated with carboplatin plus paclitaxel or cisplatin (n = 6). Leukoencephalopathy may follow on from acute encephalopathy, but may also be the first indication of neurotoxicity several months to years after administration of cytotoxic drugs. Paola Marmiroli, Shire (I), Acetylon Pharmaceuticals (I), Methys (I). The ECOG criteria are organized in a similar manner with a scale from 0 to 4 and can be viewed at www.ecog.org. Patients with HIV-related malignancies are also at increased risk of cytotoxic-induced neuropathy, since both HIV and the drugs used to treat it (highly active antiretroviral therapy, or HAART) can cause neurological damage independently. The neuropathy tends to be predominantly sensory in nature, with a glove and stocking distribution. Troublesome symptoms in cancer survivors: fatigue, insomnia, neuropathy, and pain, Qualitative research into the symptom experiences of adult cancer patients after treatments: a systematic review and meta-synthesis, The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings, Chemotherapy-induced peripheral neurotoxicity assessment: a critical revision of the currently available tools, Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention, Cognitive changes associated with cancer and cancer treatment. The previously accepted paradigm that CIPN, in nearly all cases, is a reversible clinical condition has recently been challenged by several studies performed mainly in patients with breast, colorectal, and ovarian cancer, in which the use of neurotoxic drugs is frequent and survival for greater than 5 years is increasingly frequent. More rarely, patients can develop inflammatory demyelinating polyneuropathy, mononeuritis multiplex, or neuronal damage due to opportunistic infections such as CMV and HZV. Patients report problems with memory retrieval, learning, and concentration, which may persist after treatment has finished or never fully resolve. Asparaginase acts to cleave asparagine, an essential amino acid required by rapidly proliferating cells (hence its antimitotic action) and also as a neurotransmitter. Risk factors include extremes of age, dose/ schedule, previous cranial radiotherapy, and renal or hepatic dysfunction.8,9. Methotrexate is one of the most widely used cytotoxic antimetabolites in the treatment of hematological, breast, and head/ neck cancers. The alterations in the normal activity of the nervous system result in the damage. Ifosfamide induced encephalopathy Symptoms: disorientation, hallucination, catatonia, seizures and gradually worsening sensorium lapsing into coma circulatory collapse and death The risk of development advanced age, hepatic dysfunction, impaired renal function, oral use of ifosfamide and concomitant use of other central nervous systems depressants Jain S, 2001 x very active metabolism … No effective treatments are available for alleviating persistent symptoms of chemotherapy-induced peripheral neurotoxicity. Expert Testimony: None. It has been suggested that some of their neurotoxic effects are a result of the capacity to interact with the immune system. The risk of neurotoxicity is increased by age, dose/ schedule (particularly cumulative dose), renal or hepatic impairment, and the concurrent use of neurotropic antiemetics such as phenothiazines.8,75,76, The mechanism of toxicity is not well-understood, but it appears that cytarabine directly causes neuronal death, possibly by the inhibition of cytidine-dependent neurotropic signal transduction,77 although it has also been shown to stimulate the production of reactive oxygen species that may also damage DNA directly by inducing strand breaks.78, Acute cerebellar dysfunction is the commonest central neurotoxicity, occurring in approximately 14% of patients; they typically present with dysarthria, nystagmus, gait ataxia, and confusion. Patients typically complain of a numbness and tingling sensation in the extremities, specifically in the fingers, toes, and feet. Behavioral signs include acute psychosis, restlessness, wide mood swings with inappropriate crying and laughing, cortical blindness, visual hallucinations, stupor, and akinetic mutism … Loss of neurological function may progress upwards.23 Histologically, there are focal areas of necrosis, particularly at the periphery of the spinal cord, associated with axonal swelling and demyelination. However, despite the better regeneration capacity of the peripheral nervous system (PNS), PNS neurotoxicity also can be severe and permanent. The overall incidence of these toxicities is unknown, but they are becoming more common with the escalations in cytotoxic dose that are now possible with modern hydration regimens, and the use of growth factor support and/or peripheral blood stem cells rescue to prevent myelosuppression. However, it can result in painful and dose-limiting neurotoxic side effects such as hand-foot syndrome and chemotherapy-induced peripheral neuropathy. The painful symptoms associated with chemotherapy-induced neurotoxicity can impact efficacy due to dose reduction or lead to … Generally, symptoms are self-limiting, but in some patients the symptoms persist. Neurotoxicity occurs when the exposure to natural or manmade toxic substances (neurotoxicants) alters the normal activity of the nervous system. They also cause cell-cycle kinetics alterations: postmitotic DRG neurons would reenter into the cell cycle and be induced into apoptosis.15 Other pathogenetic hypotheses have been proposed, which involve oxidative stress, mitochondrial dysfunction, reduction in the activity of enzymes involved in DNA base excision, repair of oxidative damage, redox regulation, and cellular transport.16–18, The most obvious mechanism of PNS damage by taxanes is related to their hyper-polymerizing action on microtubules. Methotrexate is one of the most widely used cytotoxic antimetabolites in the treatment of hematological, breast, and head/ neck cancers.9 In addition, prophylactic intrathecal use in ALL and high grade non-Hodgkin lymphomas has reduced the incidence of CNS relapse in high risk patients.97 Methotrexate acts by inhibiting dihydrofolate reductase, thus blocking purine and thymidine biosynthesis. CIPN pathogenesis is still unclear for many aspects, and most of the available information relies on the results of preclinical models. Cyclophosphamide is a prodrug, which alkylates DNA after hepatic activation. Patients report problems with memory retrieval, learning, and concentration, which may persist after treatment has finished or never fully resolve.1 The incidence of acute problems during treatment ranges from 15% to 70%, with 50% of patients in one study identifying persistent problems a year after treatment.2 Cross-sectional studies also suggest persistent cognitive dysfunction in 20% to 30% of patients 2 to 10 years posttreatment.3,4. On this basis, it is likely that taxanes and epothilones share the same mechanism of damage.11, Vinca alkaloid neurotoxicity is probably related to their ability to inhibit microtubule functions and disrupt the cytoskeleton.11 In neurons, vinca alkaloids prevent tubulin polymerization from soluble dimers into microtubules, which leads to axonal swelling and alteration of the axonal transport.22 The different affinity for tubulin shown by vinca alkaloid compounds (vincristine affinity > vinblastine > vinorelbine > vinflunine) might explain the distinct neurotoxic profile of these drugs.11, DRG neurons, satellite cells, and nerve fibers also are targets of bortezomib toxicity.23,24 In animal models, bortezomib causes a severe DRG neuronal dysfunction that not only inhibits proteasome activity but also alters transcription, nuclear processing and transport, and cytoplasmic translation of mRNA.25 In the peripheral nerves, histopathologic and neurophysiologic findings demonstrate a dose-dependent damage of B and C fibers with abnormal vesicular inclusion bodies in unmyelinated axons.23,24 Mitochondrial and endoplasmic reticulum damage and dysregulation of neurotrophins, caused by either activation of the mitochondrial-based apoptotic pathway or inhibition of the transcription of factors necessary for neuron survival, also have been reported.26 Recently, increased tubulin polymeration has been demonstrated in cultured DRG neurons and in animal models.27,28, Despite the evident neurotoxic effects of thalidomide,29 no convincing pathogenetic explanation for thalidomide neurotoxicity has been provided, and its more recent and highly active derivatives lenalidomide and pomalidomide are definitely less neurotoxic.30, At the moment, no effective preventive or curative strategy is available for the treatment of CIPN, as documented by a systematic Cochrane review of platinum drugs.31 A focused American Society for Clinical Oncology (ASCO) expert panel extended this review substantially to the other neurotoxic drugs, with the same disappointing results.32. Editorial Roster Patients with CIPN can experience negative (i.e., impairment in touch, pin and vibration perception, sensory ataxia with imbalance and falls) as well as positive (i.e., paresthesias/dysesthesias, neuropathic pain) symptoms. The first methodological study designed to address this relevant issue has been reported recently,4 and marked differences in perceptions of CIPN by patients versus by treating physicians have been demonstrated.14 These apparently conflicting results actually represent two sides of the same coin, and they should always be coupled in the planning and interpretation of any study devoted to CIPN investigation or treatment. depending on the chemotherapy. 54, 55 Symptoms tend to resolve spontaneously within a few days of treatment cessation although administration of thiamine may be helpful. DOI: 10.14694/EdBook_AM.2015.35.e553 American Society of Clinical Oncology Educational Book A number of trials have investigated the benefits of agents such as calcium-magnesium infusions, carbamazepine, gabapentin, amifostine, and glutathione.7,35–52 However, the trials are small studies and no specific prophylaxis can be routinely recommended. The symptoms may seem vague and unconnected, lead… Leukoencephalopathy may follow on from acute encephalopathy, but may also be the first indication of neurotoxicity several months to years after administration of cytotoxic drugs. But there are ways you and your experts can pinpoint the damage and its cause. Buy Membership for Hematology, Oncology and Palliative Medicine Category to continue reading. Examples of Peripheral Neurotoxicity of Targeted Agents Used in Cancer Therapy. Over the last decades, improvement in early diagnosis, precise subtype characterization, and more effective treatment plans allowed clinicians to achieve complete cures or remarkable increases in long-term survival in patients living with cancer in developed countries. ASCO Author Services In rarer situations, this can be due to paraneoplastic syndromes, which tend to have a subacute onset and may be associated with the presence of antineuronal antibodies. Despite these efforts, knowledge about this problem is still largely incomplete, and further studies are necessary to clarify the several still-unsettled aspects of long-term peripheral neurotoxicity of conventional and targeted anticancer chemotherapy. Several of these targeted drugs are now used routinely. Patients with HIV-related malignancies are also at increased risk of cytotoxic-induced neuropathy, since both HIV and the drugs used to treat it (highly active antiretroviral therapy, or HAART) can cause neurological damage independently.34 Distal sensory neuropathy is the commonest form of HIV-associated neuropathy and can be difficult to distinguish from that caused by specific nucleoside antiretrovirals. Paola Alberti. JCO Clinical Cancer Informatics Infusions of methylene blue are used prophylatically in patients receiving ifosfamide who have previously developed acute encephalopathy. Chemotherapy-Induced Peripheral Neurotoxicity in CancerSurvivors: An Underdiagnosed Clinical Entity? 22 Patients may also develop acute confusion in the absence of cerebellar signs, which may … If focal neurological deficit is present, CT or MRI imaging may be helpful and, in any case, should be undertaken prior to a lumbar puncture. Acute encephalopathy is associated with the administration of high-dose methotrexate (>3 mg/m, Medical Complications in the Management of Brain Tumors, Neurological Complications of Radiation Therapy. Neurotoxicity is rare, but may include acute cerebellar dysfunction in 3% to 7% of patients, causing gait ataxia, nystagmus, and scanning speech. Autonomic neuropathy can also occur and causes symptoms such as constipation, erectile dysfunction, bladder retention, and orthostatic hypotension. Acute encephalopathy is a common problem in oncology patients; it has a wide range of precipitating factors including metabolic derangements, hypoxia, brain metastases, meningeal carcinomatosis, infection, paraneoplastic phenomena, and drugs. TABLE 2. Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. The epidemiology of CIPN is still unclear, and one of the main reasons for this uncertainty is the lack of a gold standard in its assessment.5 In fact, the reliability and reproducibility of a CIPN assessment in patients with cancer are still unmet clinical and scientific needs. MRI scanning reveals diffuse high-intensity lesions within the central matter on T2-weighting that may be reversible.18 The encephalopathy should rapidly resolve entirely on stopping cytarabine; however, damage may be permanent and progress to leukoencephalopathy in a minority of patients, usually those with preexisting organ dysfunction or neurological problems.8 Less commonly, optic neuropathy, anosmia, and an incompletely reversible myelopathy have been reported.14 As with methotrexate, the intrathecal administration of cytarabine may cause ascending myelitis.8,79–81 There have also been case reports of sensory peripheral neuropathy following cytarabine exposure.82, Etoposide, a topoisomerase II inhibitor used in treatment of hematological, lung, ovarian, and testicular cancers,69 causes very little neurotoxicity, although at very high doses there have been reports of peripheral neuropathy, headache, seizures, and somnolence, in bone marrow transplant recipients and patients with malignant gliomas.83,84, Neurotoxicity with the antimetabolite fludarabine is uncommon, but somnolence, acute encephalopathy, and chronic leukoencephalopathy progressing to coma and death have all been reported.85. Different from chemotherapy with curative intent, cancer-targeted drugs also are used as continuous administration after treatment response, and maintenance therapy can be continued in cases of tumor progression to prevent uncontrolled growth. Once diagnosed, the asparaginase should be stopped and the patient anticoagulated unless hemorrhage is present. The relationship existing between patients with cancer and their health-care providers is somewhat complex. Permissions, Authors However, the peripheral nervous system also can be permanently damaged by anticancer treatments despite its better regeneration capacities, and the effect on patients' daily life activities might be extremely severe. Moreover, patients often are worried by the possibility that effective treatment could be modified because of side effects. Andreas Argyriou. In the past, several methodological issues were not clearly recognized, and different nonvalidated scales were used, which led to conflicting results. CancerLinQ Enter words / phrases / DOI / ISBN / authors / keywords / etc. In patients with CIPN who are treated with platinum drugs, a peculiar temporal pattern can be observed, which is represented by symptoms that worsen months after chemotherapy suspension—the so-called coasting phenomenon. Thrombosis typically occurs within the dural sinuses and cerebral veins, leading to secondary hemorrhage or infarction.67 Patients present with a range of symptoms from mild headache to coma and death, which are caused by rapid increases in intracranial pressure. In this clinical setting, a formal trial (the CI-PeriNomS study) demonstrated the actual reliability of physician-assessed and patient-reported outcome measures in patients with stable CIPN. Spinal cord toxicity can occur following intrathecal administration of certain cytotoxics in acute leukemias, lymphomas, and brain tumors. Acute encephalopathy is associated with the administration of high-dose methotrexate (>3 mg/m2) and is characterized by somnolence, confusion, and seizures.98 Other symptoms include emotional lability and alternating hemiparesis, giving rise to the misdiagnosis of a functional disorder. Acute encephalopathy is a common problem in oncology patients; it has a wide range of precipitating factors including metabolic derangements, hypoxia, brain metastases, meningeal carcinomatosis, infection, paraneoplastic phenomena, and drugs.6 Presenting symptoms typically include lethargy, confusion, somnolence, seizures, or coma. Cindy Lin. Central Neurotoxicity, Memory Loss, and Their Relationship to Chemotherapy Neurotoxicity Includes: Confusion , Cognitive Problems , Memory Problems , and Seizures Currently there are few therapies able to prevent neurological toxicity preemptively. In a study that was not included in the previous review by Mols et al, Tofthagen et al investigated a cohort of patients treated with oxaliplatin up to 7 years after treatment and observed that 89% of them reported at least one symptom of neuropathy;45,46 among these patients, 24% had difficulties in driving and 60% in exercising. Onset usually occurs during administration of a multi-day regimen, particularly above a cumulative dose of 36 g/m2 and generally resolves rapidly once cytarabine is withdrawn.8,9,14 However, toxicity may be permanent once more than 8% to 20% of Purkinje cells have been lost.8 Acute encephalopathy is also common, presenting with somnolence or seizures. Patients present with cognitive deficits, which may progress to dementia, coma, and death.