Capecitabine-related neurotoxicity presenting with agraphia.

INTRODUCTION: Capecitabine is a pre-metabolite of 5-fluorouracil and is used as a chemotherapeutic agent. Among the common side effects of capecitabine, there are gastrointestinal side effects including nausea, vomiting, and diarrhea, and dermatological side effects including hand-foot syndrome and skin pigmentation change. However, neurological side effects of capecitabine are very rare. We describe herein a patient who developed neurological side effects in the form of agraphia and dysarthria on the 7th day of capecitabine treatment. CASE REPORT: A 34-year-old male patient, who was being followed up with the diagnosis of colon cancer, presented with speech and writing disorder that developed while under capecitabine treatment. Dysarthria and agraphia were detected in his neurological examination. Diffusion-weighted magnetic resonance imaging (MRI) revealed acute diffusion restriction in the splenium of the corpus callosum and at the level of the bilateral centrum semiovale. Brain MRI revealed symmetrical T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) signal increases at the right temporoparietal medial, corpus callosum level, and bilateral white matter level. MANAGEMENT & OUTCOME: The capecitabine treatment was terminated, and methylprednisolone treatment was administered and plasmapheresis procedure was carried out. Subsequently, significant improvement was observed in the clinical findings and neuroimaging. DISCUSSION: Capecitabine is used as an oral agent; thus, it provides ease of use. Neurological side effects associated with the use of capecitabine reportedly occur very rarely. The findings of this case demonstrated that leukoencephalopathy can be seen during the use of capecitabine, imaging results are very important in the diagnosis of leukoencephalopathy, and improvement can be achieved with the termination of the capecitabine treatment.

Irinotecan-associated dysarthria: A single institution case series with management implications in patients with gastrointestinal malignancies.

Irinotecan (Camptosar©, CPT-11), a topoisomerase I inhibitor, is a commonly used cytotoxic chemotherapeutic in the treatment of multiple malignancies, particularly of gastrointestinal origin. Dysarthria secondary to irinotecan has been described as a rare side effect in a few case reports with limited data to recommend appropriate management. We describe herein a large single institution experience of patients with gastrointestinal malignancies who experienced dysarthria while being treated with irinotecan-based chemotherapy regimens (FOLFIRINOX or FOLFIRI+/-bevacizumab). Eighteen patients developed neurological manifestations during irinotecan infusion with the majority ( n = 17) developing dysarthria. Patients also experienced other known side effects including cholinergic effects (abdominal bloating, diarrhea, facial flushing, diaphoresis, and rhinorrhea), nausea, fatigue, perioral paresthesia and musculoskeletal discomfort. The dysarthria occurred as early as with the first infusion of irinotecan ( n = 9), but several patients did not develop symptoms until subsequent infusions (range, 1-6). Dose alterations of irinotecan did not obviously impact the reccurrence or severity of dysarthria. Management strategies included close observation, atropine, slower irinotecan infusion rate, and reassurance. Dysarthria resolved without consequence in all patients within hours of completion of the infusion. Oncologists and pharmacists should be aware of irinotecan-associated dysarthria as a rare, self-limited phenomenon with no long-term sequelae, and appropriately counsel patients and infusion nurses to avoid inadvertently withholding potentially beneficial therapy for patients with gastrointestinal malignancies.

Subacute Methotrexate Encephalopathy Mimicking Ischemic Stroke With Dynamic Changes on Magnetic Resonance Imaging.

We report a 35-year-old woman who suddenly developed left hemiparesis and dysarthria at 13days after treatment with intrathecal and intravenous methotrexate for intravascular large B cell lymphoma with possible central nervous system infiltration. Seven hours after onset, she developed further right hemiparesis and aphasia. However, the majority of neurologic symptoms disappeared spontaneously and completely by 34hours. We also recorded the dynamic progression and regression of abnormal signals in the bilateral corona radiata on diffusion-weighted imaging, in parallel with neurologic symptoms. The rapid reversal of MR abnormalities and neurologic symptoms allowed us to diagnose methotrexate encephalopathy, and exclude intravascular large B cell lymphoma recurrence and regular brain infarction. The case provides new data on the dynamic changes of abnormal signals on magnetic resonance imaging in methotrexate encephalopathy over a short recovery time.

Irinotecan-induced dysarthria: A case report and review of the literature.

Irinotecan-induced dysarthria has been reported in the literature, but the underlying mechanism of this neurotoxicity remains unclear. Here, we present a 35-year-old female with metastatic colon cancer who experienced dysarthria during irinotecan infusion. Her symptoms were decreased and eventually eliminated with subsequent increases in infusion time. When the patient returned to original 90 min infusion time, symptoms were significantly reduced in both severity and duration as compared to the first infusion. We suggest infusion time as a potential intervention for patients experiencing dysarthria, and we review the existing literature, explore treatment options, and discuss proposed mechanisms surrounding this unusual adverse drug reaction.

Metronidazole-Induced Encephalopathy in Alcoholic Liver Disease: A Diagnostic and Therapeutic Challenge.

BACKGROUND: Acute encephalopathy in a patient with alcoholic liver disease (ALD) is a commonly encountered emergency situation occurring most frequently due to liver failure precipitated by varying etiologies. Acute reversible cerebellar ataxia with confusion secondary to prolonged metronidazole use has been reported rarely as a cause of encephalopathy in patients with ALD. CASE REPORT: We describe a decompensated ALD patient with recurrent pyogenic cholangitis associated with hepatolithiasis who presented to the emergency department with sudden-onset cerebellar ataxia with dysarthria and mental confusion after prolonged use of metronidazole. Magnetic resonance imaging (MRI) of the brain was suggestive of bilateral dentate nuclei hyper intensities on T2 and fluid-attenuated inversion recovery sections seen classically in metronidazole-induced encephalopathy (MIE). Decompensated liver cirrhosis resulted in decreased hepatic clearance and increased cerebrospinal fluid concentration of metronidazole leading to toxicity at a relatively low total cumulative dose of 22 g. Both the clinical symptoms and MRI brain changes were reversed at 7 days and 6 weeks, respectively, after discontinuation of metronidazole. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: A patient with ALD presenting with encephalopathy creates a diagnostic dilemma for the emergency physician regarding whether to continue metronidazole and treat for hepatic encephalopathy or to suspect for MIE and withhold the drug. Failure to timely discontinue metronidazole may worsen the associated hepatic encephalopathy in these patients. Liver cirrhosis patients have higher mean concentration of metronidazole and its metabolite in the blood, making it necessary to keep the cumulative dose of metronidazole to < 20 g in them.

Olanzapine long-acting injection: a review of first experiences of post-injection delirium/sedation syndrome in routine clinical practice.

BACKGROUND: Olanzapine long-acting injection (LAI) for the treatment of schizophrenia was associated with a cluster of symptoms termed post-injection delirium/sedation syndrome (PDSS) in a small percentage (~2%) of patients during clinical trials. The objective of this analysis was to evaluate the rate and clinical characteristics of PDSS since olanzapine LAI entered commercial use. METHODS: Cases of PDSS were identified from all reported adverse events during worldwide commercial use of olanzapine LAI through to 1 March 2014. Data sources included two ongoing post-marketing safety studies as well as spontaneously reported adverse events from routine clinical practice over a 5-year period (1 March 2009 to 1 March 2014). RESULTS: A total of 338 PDSS events were identified. Of these, 91% occurred within 1 hour of injection, and 52% of these occurred within 15 minutes. None of the PDSS events in this analysis were fatal, and most resolved within 72 hours. The most common symptoms (occurring in >30% of cases) were sedation (61%), confusion (56%), dysarthria (54%), somnolence (46%), dizziness (45%) and disorientation (35%). Overall, PDSS occurred with approximately 0.07% of injections and in 0.46-1.03% of patients (reporting and incidence rates from spontaneous reports and post-marketing safety studies, respectively). CONCLUSIONS: The PDSS events reported during routine clinical use of olanzapine LAI are generally similar in incidence and presentation to those reported in clinical trials. Caution should be applied when interpreting spontaneously reported rates of adverse events, however, due to potential under-reporting. Implemented risk-minimisation activities may contribute substantially to the identification and appropriate management of patients with PDSS in clinical practice.

A curious case of oxaliplatin-induced neurotoxicity: recurrent, self-limiting dysarthria.

This report presents a unique case of oxaliplatin-induced neurotoxicity featuring acute, recurrent, self-limiting dysarthria following multiple subsequent infusions of oxaliplatin. A 65-year-old man started chemotherapy for metastatic pancreatic adenocarcinoma with oxaliplatin-irinotecan-leucovorin-5-fluorouracil (FOLFIRINOX). During the first and subsequent infusions of oxaliplatin, the patient developed episodes of dysarthria that lasted between 2 and 4 h after oxaliplatin infusions, followed by their complete and uneventful resolution. A thorough neurological examination showed no new neurologic deficits except for very fine tongue fasciculations. Recognizing this self-limiting toxic effect of oxaliplatin is important in order to avoid dose reductions that may affect clinical outcomes.

Inability to walk, disequilibrium, incoherent speech, disorientation following the instillation of 1% cyclopentolate eyedrops: case report.

A 4-year-old boy, who had no prior history of convulsions, presented with inability to walk, disequilibrium, dysarthria (incoherent speech), and impaired cognition (disorientation) following the instillation of 1% cyclopentolate, a commonly used mydriatic in pediatric practice. This case demonstrates the uncommon, although serious, atropine-like adverse effect of cyclopentolate eyedrops in usual dosage in child.

Mutism and persistent dysarthria due to tacrolimus-based immunosuppression following allogeneic liver transplantation.

Tacrolimus is a potent immunosuppressant medication with a low therapeutic index. We report a case of mutism with persistent dysarthria in a patient receiving tacrolimus-based immunosuppression following allogeneic liver transplantation. A 59-year-old female patient with end-stage liver disease secondary to primary sclerosing cholangitis underwent successful allogeneic liver transplantation. The patient was started on tacrolimus for prevention of allograft rejection and subsequently developed complete mutism. Following consultation of the medical toxicology service, tacrolimus was discontinued and the patient's mutism gradually improved. However, the patient still has moderate dysarthria more than 2 years after tacrolimus discontinuation. The Naranjo probability scale revealed a probable adverse reaction of mutism and dysarthria associated with tacrolimus therapy. Mutism is an uncommon complication of calcineurin inhibitors. Both cyclosporine and tacrolimus have been associated with mutism, though mutism may be more common in patients treated with tacrolimus. The mechanism of injury has not been delineated, although liver transplant patients and patients with preexisting hepatic encephalopathy or neurologic disease may be at increased risk for this complication. The mainstay of treatment is tacrolimus dose reduction or discontinuation, although benzodiazepine therapy may be beneficial in the treatment of this disorder. Clinicians should be aware of the potential adverse effects associated with calcineurin inhibitor toxicity in transplant patients and should advocate for aggressive and rapid treatment of this serious adverse drug effect.

[A case of sigmoid colon cancer with temporary dysarthria associated with irinotecan].

A40 -year-old woman visited our hospital with adenocaricinoma of the sigmoid colon with multiple liver metastases and ovarian metastasis. Because of a stenosis of the primary tumor, she underwent a colostomy before chemotherapy. 5-fluorouracil and irinotecan and leucovorin(FOLFIRI)was selected as first-line chemotherapy. At the start of chemotherapy, just after the end of irinotecan and leucovorin administration, the patient developed dysarthria. There were no neurological abnormalities or hematological abnormalities. The treatment was temporarily discontinued, and the dysarthria completely disappeared within 90 minutes. 5-fluorouracil was administered after the disappearance of dysarthria. Within 60 minutes of the administration of irinotecan and leucovorin at the second chemotherapy treatment, the patient developed dysarthria again. The patient had no neurological or hematological abnormalities. Magnetic resonance imaging(MRI)showed no abnormalities. The treatment was stopped and dysarthria disappeared within 60 minutes as it did the first time. At each time, no treatment for dysarthria was performed. This patient refused to continue irinotecan because of dysarthria. Therefore, chemotherapy without irinotecan was continued for the third time onward. In the previous literature, 8 cases of dysarthria caused by irinotecan were reported as a rare toxicity. In all cases, dysarthria was temporary and reversible. Because the mechanism of dysarthria is unclear, specific treatment and precaution for dysarthria is not recommended. Since dysarthria is reversible, however, irinotecan might be continued until progression.

Metronidazole-induced reversible cerebellar dysfunction.

A 73-year-old man who presented with fever and abdominal discomfort was diagnosed to have a liver abscess. He was treated with antimicrobials which included metronidazole. One month into treatment, he developed neurological symptoms and signs that were suggestive of cerebellar pathology. MRI of the brain showed T2/fluid attenuated inversion recovery hyperintensities involving bilateral dentate, fastigial and interpositus nuclei. After excluding common aetiologies, the possibility of metronidazole-induced neurotoxicity was considered. After stopping metronidazole, his symptoms and signs resolved. A subsequent MRI scan of the brain showed reversal of changes. Neurotoxicity caused by metronidazole is an uncommon adverse effect of a commonly used antimicrobial drug and should be considered in the appropriate clinical scenario.

Irinotecan-Associated Dysarthria in Patients with Pancreatic Cancer: A Single Site Experience.

BACKGROUND Irinotecan, a topoisomerase I inhibitor, is a cytotoxic chemotherapeutic agent used to treat multiple malignancies, including those of colorectal, pancreatic, cervical, esophageal, gastric, and lung origin. Dysarthria, a state of difficult or unclear articulation of speech, has been reported as a rare side effect of irinotecan through multiple case reports and case series, but with limited published data aimed at understanding the underlying mechanism and effective management strategies. CASE REPORT We describe herein 3 cases of patients with pancreatic malignancy who experienced dysarthria while being treated with a chemotherapy regimen containing irinotecan at an ambulatory outpatient satellite chemotherapy site. All patients described received first-line FOLFIRINOX for pancreatic cancer and experienced dysarthria during their first infusion of irinotecan. In all cases, dysarthria was observed as a transient adverse drug reaction within the first 10 to 70 min of irinotecan infusion, which resolved rapidly upon pausing infusion without any long-term sequalae. All patients remained conscious and alert; physical and neurological examinations at dysarthria onset revealed no abnormalities. Some patients experienced distal extremity paresthesia, a known manifestation of oxaliplatin-induced acute neurotoxicity, and diaphoresis and nausea. Increased infusion time effectively prevented dysarthria during subsequent infusions. CONCLUSIONS Oncologists, pharmacists, nurses, and other care team members should be aware that irinotecan-associated dysarthria is a rare, mild, and self-limiting phenomenon to avoid inadvertently altering or withholding therapy. We suggest extending irinotecan infusion time, as opposed to dose reduction or treatment discontinuation, as a practical clinical management strategy for patients who develop recurrent dysarthria secondary to irinotecan infusion.

Articulation lost in space. The effects of local orobuccal anesthesia on articulation and intelligibility of phonemes.

Motor speech requires numerous neural computations including feedforward and feedback control mechanisms. A reduction of auditory or somatosensory feedback may be implicated in disorders of speech, as predicted by various models of speech control. In this paper the effects of reduced somatosensory feedback on articulation and intelligibility of individual phonemes was evaluated by using topical anesthesia of orobuccal structures in 24 healthy subjects. The evaluation was done using a combination of perceptual intelligibility estimation of consonants and vowels and acoustic analysis of motor speech. A significantly reduced intelligibility was found, with a major impact on consonant formation. Acoustic analysis demonstrated disturbed diadochokinesis. These results underscore the clinical importance of somatosensory feedback in speech control. The interpretation of these findings in the context of speech control models, neuro-anatomy and clinical neurology may have implications for subtyping of dysarthria.

False-photosensitivity and transient hemiparesis following high-dose intravenous and intrathecal methotrexate for treatment of acute lymphoblastic leukemia.

We describe a patient who was treated with high-dose intravenous and intrathecal methotrexate for acute lymphoblastic leukemia, and who manifested a false photosensitivity reaction with no prior evidence of sun exposure. This patient later experienced delayed transient hemiparesis following methotrexate administration, although without long-term sequelae. The etiology of these events is obscure, but suggestive of a vasculitic or immune-mediated reaction to methotrexate.