Methotrexate-induced subacute myelopathy: a serious but treatable complication.

Subacute myelopathy is a rare but serious complication of methotrexate (MTX) that may cause paraplegia. Although its underlying mechanisms have not been fully elucidated, homocysteine is thought to play a role in the pathogenesis of this adverse effect. Herein, we report the case of a 34-years old female patient with diffuse large B-cell lymphoma who developed progressive paraplegia accompanied by dysfunctional bladder and bowel movements after treatment with a modified CODOX-M/IVAC regimen, including high-dose intravenous MTX and intrathecal (IT-) MTX. Neurological symptoms gradually improved to almost normal levels within 4.5 months of onset following treatment with a combination of S-adenosylmethionine, methionine, cyanocobalamin, and folate. During chemotherapy, including high-dose MTX and IT-MTX for hematological malignancies, MTX-induced subacute neuronal damage should be carefully evaluated, and appropriate treatment should be initiated as early as possible.

Severe Generalized Weakness, Paraplegia following administration of Oxaliplatin in a patient with refractory T-cell non-Hodgkin lymphoma: A case report.

INTRODUCTION: Oxaliplatin is a third-generation platinum compound that used extensively for the treatment of various types of cancer especially gastrointestinal neoplasms. The main dose-limiting toxicities of oxaliplatin are hematological toxicity and peripheral sensory neuropathy. CASE REPORT: A 42-year-old man with refractory peripheral T-cell lymphoma (PTCL) was admitted to receive GEMOX chemotherapy regimen (gemcitabine, oxaliplatin). Three days after receiving his third cycle of chemotherapy regimen, he was re-admitted to the emergency department with complaint of severe generalized weakness, and paraplegia in the lower extremities. According to clinical and para-clinical findings, chronic sensorimotor polyneuropathy with ongoing axonal loss was confirmed. MANAGEMENT & OUTCOME: Intravenous dexamethasone 8 mg three times daily was started at the time of admission for the patient. Muscle weakness and sensory impairment improved dramatically within 10 days and the patient was able to walk with assistance. DISCUSSION: Several cases of neuropathy following oxaliplatin and only one case with gemcitabine-based chemotherapy regimen have been previously reported. However, motor symptoms are rare unless in the setting of acute neuropathy due to oxaliplatin. The most striking finding of our study was the incidence of a chronic sensorimotor axonaldemyelinating polyneuropathy in a patient who were subjected to oxaliplatin therapy. In conclusion, we report a case of severe generalized weakness and paraplegia following administration of Oxaliplatin.

Serious Neurological Complication Resulting from Inadvertent Intradiscal Injection During Fluoroscopically Guided Interlaminar Epidural Steroid Injection.

We describe the case of a 30-year-old patient who was referred for lumbar epidural corticosteroid injection due to right L5 radiculopathy. Two months earlier, MRI demonstrated a right large paracentral L4-L5 disk extrusion causing disabling L5 radiculopathy. The L4-L5 level was selected for interlaminar injection, using fluoroscopic guidance. During injection, the patient developed severe pain in both lower extremities. Thus, the procedure was immediately terminated. Paraplegia occurred within several minutes. Urgent lumbar spine CT and MRI demonstrated contrast material in a massive extruded disk fragment and substantial increase in size of the disk extrusion compared to pre-injection MRI. Emergency surgery was performed for lumbar decompression and discectomy. Although rare, serious neurological complication can result from inadvertent intradiscal injection of contrast material during lumbar epidural injection. This case illustrates the importance of recognizing the possibility of dynamic change in the size of an extruded disk fragment when the MRI precedes injection by a substantial time interval. LEVEL OF EVIDENCE: IV, Case Series.

Acute progressive paraplegia in heroin-associated myelopathy.

As the opioid epidemic continues, understanding manifestations of abuse, including heroin-associated myelopathy remains essential. Here we describe a young man with a past medical history significant for polysubstance abuse who developed acute-onset, rapidly progressive myelopathy after resumption of intravenous heroin use. He had significant spinal cord involvement with findings suggestive of heroin-associated myelopathy. The salient features of this case include diffusion imaging of the spine and spinal angiography supporting a possible vasculopathy as the pathophysiologic mechanism underlying heroin-associated myelopathy. Additionally, CSF studies showed the transition from a neutrophilic pleocytosis to a lymphocytic pleocytosis suggesting an inflammatory component.

Rapid Progressive Disease After Nivolumab Therapy in Three Patients with Metastatic Renal Cell Carcinoma.

BACKGROUND/AIM: Rapid progressive disease (RPD), accelerated tumour growth immediate after the initiation of immune checkpoint inhibitor therapy, has been reported in melanoma and lung cancer. Herein, we describe 3 cases of RPD during the initial phase of nivolumab treatment for metastatic renal cell carcinoma. PATIENTS AND METHODS: The first and second patients received nivolumab in the fourth-line setting. The third patient received nivolumab therapy as third-line treatment. RESULTS: The first patient developed severe respiratory failure due to carcinomatous lymphangiosis 14 days after initiation of nivolumab therapy. The second patient developed leg paraplegia due to rapid growth of the metastatic tumour at the sixth thoracic vertebrae 5 days later. The third patient developed grade 4 hypercalcemia due to RPD on day 3. CONCLUSION: Clinicians should be aware of RPD during the initial phase of nivolumab therapy, especially in patients with critical lesions in the late-line setting.

Ringhalexin from Hemachatus haemachatus: A novel inhibitor of extrinsic tenase complex.

Anticoagulant therapy is used for the prevention and treatment of thromboembolic disorders. Blood coagulation is initiated by the interaction of factor VIIa (FVIIa) with membrane-bound tissue factor (TF) to form the extrinsic tenase complex which activates FX to FXa. Thus, it is an important target for the development of novel anticoagulants. Here, we report the isolation and characterization of a novel anticoagulant ringhalexin from the venom of Hemachatus haemachatus (African Ringhals Cobra). Amino acid sequence of the protein indicates that it belongs to the three-finger toxin family and exhibits 94% identity to an uncharacterized Neurotoxin-like protein NTL2 from Naja atra. Ringhalexin inhibited FX activation by extrinsic tenase complex with an IC50 of 123.8 ± 9.54 nM. It is a mixed-type inhibitor with the kinetic constants, Ki and Ki' of 84.25 ± 3.53 nM and 152.5 ± 11.32 nM, respectively. Ringhalexin also exhibits a weak, irreversible neurotoxicity on chick biventer cervicis muscle preparations. Subsequently, the three-dimensional structure of ringhalexin was determined at 2.95 Å resolution. This study for the first time reports the structure of an anticoagulant three-finger toxin. Thus, ringhalexin is a potent inhibitor of the FX activation by extrinsic tenase complex and a weak, irreversible neurotoxin.

Late-onset paraplegia after complete response to two cycles of ipilimumab for metastatic melanoma.

BACKGROUND: Ipilimumab has been shown to improve overall survival in patients with metastatic melanoma; however, complete responses (CRs) are uncommon. Immune-related side effects usually involve the skin or gastrointestinal tract. Neurologic events occur less frequently but are well described. CASE REPORT: We report the case of a 58-year-old man with metastatic melanoma who commenced ipilimumab post spinal decompression and radiation. He developed a colitis post cycle 2 and ipilimumab was discontinued. Imaging, however, documented a radiological CR. 8 weeks later, he developed paraplegia and a myelitis despite an ongoing radiological CR. Steroid use resulted in some improvement radiologically, without clinical improvement. CONCLUSION: We report myelitis with consequent paraplegia as a potential neurological immune-related side effect of ipilimumab. We further describe a patient with a CR after 2 cycles of ipilimumab in the setting of radiation.

A novel arrangement of Cys residues in a paralytic peptide of Conus cancellatus (jr. syn.: Conus austini), a worm-hunting snail from the Gulf of Mexico.

The present study details the purification, the amino acid sequence determination, and a preliminary characterization of the biological effects in mice of a new conotoxin from the venom of Conus cancellatus (jr. syn.: Conus austini), a worm-hunting cone snail collected in the western Gulf of Mexico (Mexico). The 23-amino acid peptide, called as25a, is characterized by the sequence pattern CX1CX2CX8CX1CCX5, which is, for conotoxins, a new arrangement of six cysteines (framework XXV) that form three disulfide bridges. The primary structure (CKCPSCNFNDVTENCKCCIFRQP*; *, amidated C-terminus; calculated monoisotopic mass, 2644.09Da) was established by automated Edman degradation after reduction and alkylation, and MALDI-TOF and ESI mass spectrometry (monoisotopic mass, 2644.12/2644.08Da). Upon intracranial injection in mice, the purified peptide provokes paralysis of the hind limbs and death with a dose of 240 pmol (~0.635 µg, ~24.9 ng/g). In addition, a post-translational variant of this peptide (as25b) was identified and determined to contain two hydroxyproline residues. These peptides may represent a novel conotoxin gene superfamily.

Inadvertent epidural injection of drugs for intravenous use. A review.

INTRODUCTION: The frequency of inadvertent injection of drugs in the epidural space is probably underestimated and underreported, but it can cause serious morbidity and possibly mortality. OBJECTIVE: The aim of this review is to collate reported incidents of this type, to describe the potential mechanisms of occurrence and to identify possible therapeutic solutions. METHODS: We searched into medical databases and reviewed reference lists of papers retrieved. RESULTS: A list is reported of more than 50 drugs that were inadvertently injected into the epidural space. This list includes drugs which produce no, little or short-lasting neurological deficits, but also includes drugs that may be more etching and can result in temporary or even permanent neurological deficit. DISCUSSION: Most drugs do not lead to sequelae other than pain during injection or transient neurological complaints. Other drugs may have more deleterious consequences, such as paraplegia. Both the dose of the inadvertent injected drug and the time frame play an important role in the patient's outcome. "Syringe swap", "ampoule error", and epidural/intravenous line confusion due to inaccurate or absent colour coding of epidural catheters were the main sources of error. Preventive strategies, including non Luer-lock epidural injection ports, might increase safety.

Paraplegia and paraparesis from intrathecal methotrexate and cytarabine contaminated with trace amounts of vincristine in China during 2007.

PURPOSE: The production and administration of drugs used intrathecally requires special care to prevent contamination with neurotoxic agents. In 2007, we investigated a widespread outbreak of paraplegia and paraparesis among Chinese patients who received intrathecal drugs to identify the presumed contaminant and its source to prevent further cases. PATIENTS AND METHODS: We defined a case as onset from January 1 to October 31, 2007, of bilateral flaccid paraparesis or paraplegia or retention and incontinence of stool or urine, in a patient receiving intrathecal drugs. Using a retrospective cohort approach, we selected 12 hospitals from all hospitals that had reported cases. In these hospitals, we identified all 448 patients (including 107 cases) who received intrathecal chemotherapy or chemoprophylaxis in 2007. We calculated attack rates and Mantel-Haenszel adjusted risk ratios for intrathecal drug type and lot. RESULTS: All 12 hospitals used intrathecal methotrexate or cytarabine produced by one pharmaceutical plant. Only two lots of each drug were associated with cases. Lot-specific attack rates ranged from 42% to 100% (risk ratio, ∞; lower confidence bounds, 1.8 to 7.3). Vincristine production had immediately preceded production of the implicated lots on the same equipment. By using ultra performance liquid chromatography, we detected vincristine (0.28 to 18 µg) in unused vials from implicated lots of methotrexate and cytarabine. CONCLUSION: Trace amounts of vincristine that contaminated intrathecal drugs caused a large outbreak of severe neurologic damage. Vincristine and other neurotoxic drugs should not be produced on any equipment that is also used for producing drugs that are to be administered intrathecally.

A medical-legal review regarding the standard of care for epidural injections, with particular reference to a closed case.

Interventional pain management is an evolving field, with a primary focus on the safety of the patient. One major source of risk to patients is intraarterial or intraneural injections. Interventional pain physicians have considerable interest in identifying techniques which avoid these complications. A recent article has reviewed complications associated with interventional procedures and concluded that the complications were due to deviation from a specific prescribed protocol. One of the cases reviewed went to jury trial and the record of that case is in the public domain. Two of the authors of the recent review were expert witnesses in the trial. They provided conflicting testimony as to alleged violations of the standard of care. Their criticisms also differed from a third criticism contained in the article as well as the protocol being advocated in the article, thus contravening the claim that there is one prescribed protocol which must be followed. The definition of standard of care varies amongst jurisdictions, but is generally defined as either that care which a reasonably well-trained physician in that specialty would provide under similar circumstances or as what would constitute reasonable medical care under the circumstances presented. Analysis of the case which went to trial indicates that there is not one prescribed protocol which must be followed; the definition of standard of care is broader than that. Interventional pain management is an evolving field and the standard of care is broadly defined.

Oxidised regenerated cellulose: an unusual cause of paraplegia following oesophagectomy.

Oesophageal resection after neoadjuvant therapy is the treatment of choice in localized oesophageal cancer. Common complications after oesophagectomy include pulmonary infection and anastomotic leaks. Paraplegia or paraparesis after oesophagectomy is an extremely uncommon occurrence and has not been reported in medical literature. Possible causes include injury to the spinal cord due to epidural catheter insertion, epidural haematoma and anterior spinal artery thrombosis. Pressure on the spinal cord due to migrated oxidised regenerated cellulose (ORC) is an extremely rare cause. Meticulous haemostasis at the costovertebral angle with a combination of pressure and electrocautery is advocated to prevent this rare but catastrophic complication. We describe a middle aged woman who developed post-thoracotomy paraplegia following ORC compression on the spinal cord.

Paraplegia following image-guided transforaminal lumbar spine epidural steroid injection: two case reports.

OBJECTIVE: To present two case reports of a rare but devastating injury after image-guided, lumbar transforaminal injection of steroids, and to explore features in common with previously reported cases. BACKGROUND: Image (fluoroscopic and computed tomography [CT])-guided, lumbar transforaminal injections of corticosteroids have been adopted as a treatment for radicular pain. Complications associated with these procedures are rare, but can be severe. CASE REPORTS: An 83-year-old woman underwent a fluoroscopically guided, left L3-L4, transforaminal injection of betamethasone (Celestone Soluspan). A 79-year-old man underwent a CT-guided, right L3-L4, transforaminal injection of methylprednisolone (DepoMedrol). Both patients developed bilateral lower extremity paralysis, with neurogenic bowel and bladder, immediately after the procedures. Magnetic resonance imaging scans were consistent with spinal cord infarction. There was no evidence of intraspinal mass or hematoma. CONCLUSION: These cases consolidate a pattern emerging in the literature. Distal cord and conus injury can occur following transforaminal injections at lumbar levels, whether injection is on the left or right. This conforms with the probability of radicular-medullary arteries forming an arteria radicularis magna at lumbar levels. All cases used particulate corticosteroids, which promotes embolization in a radicular artery as the likely mechanism of injury. The risk of this complication can be reduced, and potentially eliminated, by the utilization of particulate free steroids, testing for intra-arterial injection with digital subtraction angiography, and a preliminary injection of local anesthetic.