Serotonergic antidepressants and linezolid: a retrospective chart review and presentation of cases

OBJECTIVE: To report the results from a retrospective chart review looking at the combination of linezolid and serotonergic antidepressants and to report two cases of serotonin syndrome which were identified at our hospital. Case SUMMARY: During the retrospective chart review one case of serotonin syndrome was identified. A 65-year-old female was receiving escitalopram for the treatment of depression prior to admission. Linezolid therapy was initiated on admission and two days later the patient had a tonic-clonic seizure. Escitalopram was discontinued and the patient did not have any further seizure activity. In a second case, a 37-year-old male was receiving citalopram during hospitalization and was started on concomitant linezolid. The patient had myoclonus and was observed to be tremulous throughout therapy with linezolid. Ten days after discontinuation of linezolid the patient continued to have symptoms until the withdrawal of citalopram. The Naranjo probability scale scores the first case as possibly related and the second case as probably related to the combination. DISCUSSION: It has been well documented in the literature that the combination of linezolid and serotonergic antidepressants may cause serotonin syndrome. In this retrospective chart review only one patient of 53 (1.8%) had symptoms highly suggestive of serotonin syndrome. A second patient continued to have symptoms of serotonin syndrome even after withdrawal of linezolid. CONCLUSIONS: This retrospective review and subsequent case reports confirm the rare, but serious, potential of serotonin syndrome associated with the combination of linezolid and serotonergic antidepressants.     

Early onset probable linezolid-induced encephalopathy

Linezolid is increasingly being utilized for the treatment of Gram-positive pathogens. While neurological complications with linezolid are rare, long-term exposure can be associated with neurotoxic effects. Patients with pre-existing neurologic sequelae or risk factors, such as alcohol abuse, diabetes, or concomitant administration of chemotherapeutic agents and/or antiretroviral therapy, may be more susceptible to the development of linezolid-induced neurotoxicity. We describe a 41-year-old male who developed early onset encephalopathy after a day and a half of linezolid therapy. Our patient had at least one significant risk factor (alcoholism), making linezolid-induced encephalopathy probable based upon the Naranjo probability scale. Clinicians should be aware of the potential for early onset linezolid-induced neurotoxicity, particularly in patients with concomitant risk factors.     

Linezolid Treatment for Osteomyelitis due to Staphylococcus Epidermidis with Reduced Vancomycin Susceptibility

Limited therapeutic options are available for vancomycin intermediate-resistant Staphylococcus Epidermidis (VISE) infections and no optimum therapy has been established. We report a case of VISE skull osteomyelitis that was successfully treated with linezolid. The patient was a 53-year-old man who presented with headache, nausea and dysphasia. Brain computerized tomography (CT) demonstrated a subdural hematoma in the left hemisphere. Craniotomy and hematoma evacuation was performed and he showed good recovery despite a scalp wound infection caused by methicillin-resistant Staphylococcus aureus (MRSA). The organism isolated from the scalp wound was sensitive to vancomycin. The patient was treated with intravenous vancomycin for 44 days. However, he showed a high fever, persistent positive methicillin-resistant Staphylococcus Epidermidis (MRSE) blood cultures, and a deteriorating clinical status. He underwent infected skull bone flap removal and linezolid treatment for 35 days. During one year of follow up, he has not had any further episodes of osteomyelitis or fever. Linezolid has shown to be effective agent to eradiate osteomyelitis caused by VISE.     

Linezolid-associated toxic optic neuropathy

The oxazolidinone antimicrobial linezolid is effective against gram-positive bacteria. Although maximal recommended therapy is 28 days, treatment durations greater than this are common. Linezolid may cause reversible optic neuropathy and irreversible peripheral neuropathy after months of treatment. Three cases of linezolid-induced optic and peripheral neuropathy are described, and previously reported cases of linezolid-induced optic neuropathy are reviewed. The mechanism of neural toxicity may be impairment of mitochondrial protein synthesis.     

Cerebral mycosis: 7‐year retrospective series in a tertiary center

This study focuses on the epidemiology, clinical manifestations, risk factors, diagnosis and outcome of all cases of central nervous system (CNS) fungal infections in a tertiary center. Medical records of 18 patients of culture‐proven CNS fungal infections were retrospectively reviewed from 2000 to 2007, including 12 isolated from the cerebrospinal fluid (CSF) and seven from tissue biopsy. Patient demographic data included 10 males and eight females. The mean age was 55 years (range: 24–89 years). All but one patient were immunocompromised. Fungal organisms isolated from CSF included: Cryptococcous neoformans (8 patients), Coccidioides immitis (3 patients), and Aspergillus versicolor (1 patient). Histopathology of seven biopsy cases revealed groups of pigmented golden‐brown fungal forms in three cases; three cases showed septate fungi, two of which had melanin in their walls; and one case showed multiple round spherules. These cases on microbiological cultures grew Coccidioides immitis (1 patient), Aspergillus fumigatus (1 patient), Cladophialophora bantiana (2 patients), Fonsecaea monophora (1 patient) and Scedosporium apiospermum (2 patients). Five of the seven fungal organisms isolated from tissue biopsies were dematiaceous fungi. Twelve patients died after a period of a few weeks to months, two were lost to follow‐up, and four are alive with severe neurological sequelae. CNS fungal infections in our cohort were more common in patients post‐transplant and with hematologic malignancies. In our series, rare dematiaceous fungi are emerging agents for cerebral mycosis. The outcome of CNS fungal infections is poor despite vigorous antifungal therapy.     

Propionibacterium acnes infections after cranial neurosurgery

BACKGROUND: Propionibacterium acnes (P. acnes) is a relatively avirulent organism that is part of the normal skin flora. Most patient isolates are considered contaminants but, in a small subset of patients, particularly in the post-neurosurgery setting, the organism can cause significant infections. We reviewed our experience with the occurrence and management of P. acnes infections after cranial neurosurgical procedures over a five-year period. METHODS: Patients with positive cultures for P. acnes between 1996 and 2001 were identified by review of the Saskatoon Health Region microbiology laboratory database. Of the 141 positive cultures, a review of hospital records identified six patients with P. acnes infections after neurosurgical procedures. A review of the literature related to P. acnes associated CNS infections was conducted. RESULTS: All patients had undergone a craniotomy or burrhole placement, and one patient had received prior radiotherapy. There were no P. acnes-related ventriculoperitoneal shunt infections. All patients presented with scalp swelling and three had purulent discharge. Symptoms occurred more than two months after the initial surgery in five of six patients, while one patient developed symptoms three years post-operatively. Management for all patients included removal of the craniotomy flap and treatment with parenteral antibiotics, followed in most cases by oral antibiotics. A good response without relapse of infection was seen in five patients; one patient had recurrent infection after cranioplasty. CONCLUSIONS: P. acnes is a rare but important cause of infection after craniotomy. Wound debridement, removal of the bone flap and adequate antibiotic coverage result in cure in the majority of patients.     

Linezolid: implications for neurosurgical infections

Nosocomial infections affect a significant number of intensive care unit (ICU) patients including those in the neurosurgical ICU. Gram-positive organisms are responsible for many of these infections and often these pathogens are resistant to some of the older antimicrobial agents. Two new classes of antibiotics have been developed: streptogramins and oxazolidinones. Linezolid is an oxazolidinone, which has been shown to be effective against methicillin- and vancomycin-resistant Gram-positive pathogens. It may be administered orally or parenterally, and displays favorable pharmacokinetic properties, with rapid and complete absorption after oral administration. Linezolid is generally well tolerated with mild gastrointestinal related adverse effects. Linezolid provides a useful alternative in the treatment of Gram-positive infections, particularly those caused by resistant organisms. It has tremendous clinical utility, especially in the ICU where infections and multi-drug resistant rates are high and treatment options become limited.     

Nontuberculous mycobacterial infection of a metastatic brain neoplasm in an immunocompromised patient

BACKGROUND: Nontuberculous mycobacterial infections occur in immunocompromised patients but so rarely involve the central nervous system (CNS) that they may not be included in a differential diagnosis of CNS lesions in such patients. OBJECTIVE: To illustrate a putative mechanism for nontuberculous mycobacterial infection of the CNS via breakdown of the blood-brain barrier by metastatic neoplasm. RESULTS: A 56-year-old man who had undergone renal transplantation in February 2003 and was taking an immunosuppressive regimen of mycophenolate mofetil and cyclosporine was seen in the emergency department after a syncopal episode. Head computed tomography revealed a single focal occipital lesion with vasogenic edema. Hospital admission and further workup led to diagnosis of metastatic carcinoma infected with nontuberculous mycobacteria in the setting of a disseminated nontuberculous mycobacterial infection. CONCLUSION: This case illustrates that breakdown of the blood-brain barrier by metastatic neoplasm may provide a route of access for a pathogen that is not normally seen in the CNS.     

Treatment of primary aspergilloma of the central nervous system in a diabetic immunocompetent patient with surgical resection and voriconazole: a case report and review of the literature

Fungal infections of the central nervous system (CNS) are uncommon and occur mainly in immunocompromised patients. We describe a case of central nervous system aspergilloma without any evidence of systemic or paranasal foci in a diabetic but otherwise immunocompetent 71-year-old female treated successfully with surgical resection and medical therapy with voriconazole. Magnetic resonance imaging (MRI) after 6 months of voriconazole showed improvement and no evidence of residual or recurrent disease. Given its good CNS penetration, voriconazole along with surgical resection appears to be promising in treatment of these infections. Our case also demonstrates the importance of surgical intervention in the diagnosis and management of these atypical cases.     

Central nervous system infections in cancer patients.

In the immunocompromised patient, even mild forms of any combination of headache, meningismus, altered mental status, or focal neurologic signs should initiate an evaluation for possible CNS infection. The limited signs and symptoms of acute CNS infection are not due to specific organisms but to pathologic changes at the neuroanatomic site of infection. The initial clinical history, examination, laboratory, and neuroradiographic data will narrow the problem to one of several groups of agents, although it may not be possible to specify a single causative agent. It should be remembered that several concurrent infections (i.e., CMV and toxoplasmosis, aspergillosis, and bacterial sepsis) may be present. Thus, the clinician should rely on broad antibiotic coverage appropriate to the suspected causative agent or agents at the site of infection. It may be necessary to offer broad-spectrum antibiotic coverage for a CSF presentation that is subsequently found to result from a viral illness or from a noninfectious cause. However, one should avoid undertreating those infections for which specific therapy can be offered, and broad-spectrum treatment usually will not be regretted. Uncertainty in diagnosis following noninvasive procedures should lead to a brain biopsy. Although many of the infections discussed in this article have a poor prognosis, some of the most common pathogens, such as Cryptococcus, Listeria, and Toxoplasma, have effective specific therapies to which the patient should have access as rapidly as possible. The clinician who has successfully treated a patient with CNS infection should remain vigilant for late sequelae or recurrence of infection. Chronic treatment of some infections, such as toxoplasmosis or aspergillosis, may be necessary. The reintroduction of steroids for the treatment of an underlying cancer may reactivate previously treated disease, such as cryptococcosis, and periodic CSF surveillance is appropriate under these circumstances. Recurrence of the symptoms should raise the suspicion of recurrent or new infection, and the patient also should be evaluated with CT or MRI for the development of hydrocephalus or for new metastatic disease. In patients who have had varicella-zoster infection, postherpetic neuralgia and delayed arteritis may develop. Seizures, hearing loss, and neuropsychologic sequelae may follow any meningoencephalitis. The patient should always be reevaluated for the possibility of infection with a different opportunistic organism. CNS infections remain a major cause of morbidity and mortality in immunosuppressed patients with malignancies. In one series, 60% of such patients died as a result of their CNS infection, many at a time when the underlying disease had an otherwise good prognosis.(ABSTRACT TRUNCATED AT 400 WORDS)     

Presurgical evaluation in refractory epilepsy secondary to meningitis or encephalitis: bilateral memory deficits often preclude surgery.

We investigated the clinical features and surgical outcome of 17 patients with refractory epilepsy secondary to CNS infection who were referred to a tertiary center for presurgical evaluation. Six patients had a history of meningitis and 11 patients had a history of encephalitis. Median age at infection was three years (40 days-40 years). Time to seizure onset was shorter in the encephalitis group (median of 0.9 years versus 5.9 years in the meningitis group). MRI showed unilateral mesial temporal sclerosis (MTS) in all but one patient with meningitis (5/6). MRI in the encephalitis group showed unilateral MTS (four patients), bilateral MTS (three), porencephalic cysts (one) or no significant findings (three). Seizure semiology, following analysis of 127 seizures, included automotor seizures, complex motor/hypermotor seizures, dialeptic seizures and bilateral asymmetric tonic seizures. Neuropsychological assessment in patients with MTS frequently showed bilateral memory impairment (7 out of 12 MTS-patients), even in 4 patients with unilateral MTS, precluding epilepsy surgery. Six patients (two meningitis and four encephalitis patients) underwent a temporal lobe resection. All patients are either seizure-free (Class 1a) or are having only auras after surgery. One patient from the meningitis group underwent functional hemispherectomy and he is also seizure-free. In our series, MTS was the most common finding in refractory epilepsy after CNS infections. Bilateral memory deficits were often encountered in patients with MTS, even when unilateral, these deficits being a limiting factor for surgery. Good surgical outcome can be expected in selected patients with unilateral MTS and congruent memory deficits.     

Herpes simplex encephalitis in childhood]

Central nervous system (CNS) infection by herpes simplex virus (HSV) in childhood consists of herpes simplex encephalitis and CNS infections in neonates. Herpes simplex encephalitis in children resembles that in adults, but CNS infections in neonates differs from adult herpes simplex encephalitis in pathogenesis and clinical features. Trans-neuronal transmission by HSV type 1 causes herpes simplex encephalitis both in children and adults, while hematogeneous spread by HSV type 1 or type 2 causes CNS infections in neonates. Mortality of CNS infections by HSV in childhood has been improved since early diagnosis by polymerase chain reaction and anti-viral therapies have been established. However, neurological morbidity has not yet been improved and sometimes HSV infections relapse after the acyclovir therapy. Recently, longer acyclovir therapy with larger doses is recommended for the treatment of CNS infections in childhood.     

Fungal infections of the central nervous system in HIV-negative patients: Experience from a tertiary referral center of South India

Objective:

To describe the clinical, radiological, and cerebrovascular fluid (CSF) findings and the outcome of microbiologically or histopathologically proven fungal infections of the central nervous system (CNS) in HIV-negative patients.

Methodology and Results:

We identified definite cases of CNS mycosis by screening the medical records of our institute for the period 2000–2008. The clinical and imaging details and the outcome were abstracted from the medical records and entered in a structured proforma. There were 12 patients with CNS mycosis (i.e., 2.7% of all CNS infections treated in this hospital); six (50%) had cryptococcal infection, three (25%) had mucormycosis, and two had unclassified fungal infection. Four (33%) of them had diabetes as a predisposing factor. The common presentations were meningoencephalitis (58%) and polycranial neuritis (41%). Magnetic resonance imaging revealed hydrocephalus in 41% and meningeal enhancement in 25%, as well as some unusual findings such as subdural hematoma in the bulbocervical region, carpeting lesion of the base of the skull, and enhancing lesion in the cerebellopontine angle. The CSF showed pleocytosis (66%), hypoglycorrhachia (83%), and elevated protein levels (100%). The diagnosis was confirmed by meningocortical biopsy (in three cases), paranasal sinus biopsy (in four cases), CSF culture (in three cases), India ink preparation (in four cases), or by cryptococcal polysaccharide antigen test (in three cases). Out of the ten patients for whom follow-up details were available, six patients recovered with antifungal medications (amphotericin B, 1 mg/kg/day for the minimum period of 6 weeks) and/or surgical treatment. Four patients expired (only one of them had received antifungal therapy).

Conclusions:

Most patients with CNS mycosis recover with appropriate therapy, but the diagnosis and management of these rare infections remains a challenge to clinicians.     

Viral antibodies in the CSF after acute CNS infections.

Viral antibodies were measured in the cerebrospinal fluid (CSF) and serum from 25 patients having acute viral central nervous system (CNS) infections, and from 39 control patients. The results, collected two weeks after the clinical onset, revealed the presence of antibodies in nine of 13 (69%) CSF specimens from patients suffering from encephalitis of myelitis, and in only one of nine (11%) of the CSF samples of those presenting a viral meningitis infection. This difference was statistically significant and suggests that the titration of viral antibodies in the CSF can be helpful in establishing the diagnosis of viral CNS infection. Our data also suggest that localized production of antibodies occurs during the course of acute CNS infections, and that the respiratory syncytial virus can be associated with CNS infections in man.     

Bacterial infections of the CNS in neutropenic patients

In neutropenic patients, fever and mental status changes are frequently the only overt clinical manifestations of bacterial infections of the CNS. Prominent headache and meningeal signs are exceptional. CNS infections may occur even in patients receiving large doses of broad-spectrum antibiotics. CSF culture and Gram's stain are required to establish or exclude the diagnosis and are often positive, even in patients receiving antibiotics for other indications. The CSF cell counts and chemistries are helpful if abnormal, but, when normal, provide no assurance that infection is not present. The CSF glucose can be lowered in the absence of pleocytosis, but a low CSF glucose is neither sensitive (27% in this series) nor specific. Lumbar puncture is hazardous in many neutropenic patients because of simultaneous thrombocytopenia; lumbar puncture should be performed by an experienced physician after platelet transfusions. The outcome of CNS infection depends on the underlying clinical disorder and on bone marrow recovery. The use of third-generation cephalosporins, new semisynthetic penicillins, and intrathecal administration of aminoglycosides may improve outcome.     

Neurological complications of bone marrow transplantation in childhood

Bone marrow transplantation, used in the treatment of cancer, aplastic anemia, and metabolic diseases, involves the use of potentially neurotoxic agents to suppress immunity and eradicate malignancy. Fifty-seven patients with a median age of 11 years (age range, 6 months to 24 years) underwent bone marrow transplantation at the Children's Hospital of Philadelphia. Fifty-nine percent developed neurological abnormalities. Twenty-six patients (46%) had central nervous system (CNS) dysfunction, including infection (8), cerebrovascular accident (5), CNS leukemia (7), metabolic encephalopathy (5), and paraparesis with CNS toxoplasmosis (1). Neuropsychological dysfunction was present in 4 of 5 longterm survivors who were tested. Fourteen of 19 patients (74%) on whom postmortem examination was performed were found to have CNS abnormalities, including cerebral atrophy (10), focal cerebral injury (6), leukemia (5), and infection (3). Fourteen patients (24%) had peripheral nervous system dysfunction. CNS dysfunction was more common in patients with lymphoreticular malignancies. Cerebrovascular accidents (in patients with lymphoreticular malignancies) and infections (in our general population and in patients with lymphoreticular malignancies) occurred more often in our patients than in patients with similar illnesses who did not undergo bone marrow transplantation. The combination of prior treatment and preparative therapy for bone marrow transplantation predisposes patients to neurological and neuropsychological sequelae.     

Viruses can silently prime for and trigger central nervous system autoimmune disease

Although many viruses have been isolated from patients with multiple sclerosis (MS), as yet, no one agent has been demonstrated to cause MS. In contrast, epidemiological data indicate that viral infections are associated with exacerbations of MS. Here, we present data showing that virus infections can subclinically prime animals for central nervous system (CNS) autoimmune disease; long after the original infection has been eradicated, a nonspecific challenge/infection can trigger an exacerbation. The priming infectious agent must show molecular mimicry with self-CNS antigens such as glial fibrillary acidic protein (GFAP), myelin associated glycoprotein (MAG) or myelin proteolipid protein (PLP). The subsequent challenge, however, may be nonspecific; complete Freund's adjuvant (CFA), or infection with a recombinant vaccinia virus encoding an irrelevant protein, could trigger CNS disease. In the CNS, we could detect a mononuclear cell infiltration, but no demyelination was found. However, if the pathogenesis of MS is similar to that of this novel animal model for CNS autoimmune disease, our findings could help explain why exacerbations of MS are often associated with a variety of different viral infections.     

Staphylococcal CNS infections treated with vancomycin and rifampin

Three children had staphylococcal infections of the CNS. In two cases the organisms were resistant to methicillin sodium. Each case was treated with a combination of vancomycin hydrochloride and rifampin; in one instance vancomycin alone had been unsuccessful. The addition of rifampin resulted in prompt clinical and bacteriologic resolution. Satisfactory levels of rifampin were achieved by administering the drug either orally or intravenously, and in one patient oral administration of rifampin produced assayed levels in subdural pus many times that required for minimal bactericidal activity. Combination therapy with vancomycin and rifampin is recommended for staphylococcal infections of the CNS.     

Neuropathology and general autopsy findings in AIDS during the last 15 years

A retrospective study of 450 consecutive AIDS autopsy cases (397 males, 53 females; mean age at death 38.4 years) in Vienna, Austria, between 1984 and 1999 compares the central nervous system (CNS) findings in three cohorts: 1984–1992 (190 cases), 1993–1995 (162 cases) and 1996–1999 (98 cases, after introduction of triple antiretroviral therapy) and the relationship of CNS findings to systemic AIDS pathology in the latter two cohorts. In these two groups, following involvement of the lung (85% and 75%, respectively), the brain continued to be the second most frequently involved organ (decrease from 80% to 60%, respectively). Extracerebral protozoal (Pneumocystis carinii, toxoplasmosis), Mycobacterium avium complex, viral [e.g., cytomegalovirus (CMV)], multiple opportunistic organ and CNS infections, and Kaposi sarcoma significantly decreased over time. There was less decrease in fungal infections, while bacterial organ and CNS infections (except for mycobacteriosis), lymphomas, HIV-associated CNS lesions (around 30%), non HIV-associated changes (vascular, metabolic, etc.) and negative CNS findings (10–11%) remained unchanged. Nonspecific CNS changes (e.g., meningeal fibrosis) increased. Extracerebral pathology in subjects with advanced HIV-related CNS lesions showed more frequent but decreasing systemic bacterial and CMV infections than those with negative or nonspecific neuropathology, while other opportunistic and multiple organ infections and lymphomas showed no differences between both groups. In a cohort of drug abusers, HIV encephalitis, progressive multifocal leukoencephalopathy, bacterial infections, hepatic encephalopathy, and negative CNS findings were more frequent than in non-users who showed increased incidence of CMV, toxoplasmosis, or other opportunistic CNS infections, and nonspecific CNS findings; the frequency of lymphomas was similar in both drug abusers and non-users. Similar to a recent autopsy study from San Diego, these data suggest that despite the beneficial effects of modern antiretroviral combination therapy, involvement of the brain in AIDS subjects continues to be a frequent autopsy finding, while the increased incidence of HIV encephalitis in our small cohort of drug users was less than observed in other recent autopsy studies. Received: 7 March 2000 / Revised, accepted: 24 March 2000     

VHL相关性和散发性中枢神经系统血管母细胞瘤

目的 探讨VHL病相关性和散发性中枢神经系统(CNS)血管母细胞瘤(HB)临床、处理及预后特征。方法 回顾性分析连续20年中我科收治的66例CNS-HB病人资料。对近期病例作了VHL基因突变和VEGF表达检测。结果 66例HB病人中,散发性58例,VHL相关性8例,共79处病变,7例为多发病变。全组62例共施行了70次手术治疗,其中5例进行了多次手术。8例VHL相关病人中有3例多次手术。64次全切,6次大部分切除。大部分切除的病人有4例复发。手术死亡3人。70次手术中手术效果良好者46次,病情改善者18次,稳定者3次。57例平均随访6.7年(1～16年),41例恢复工作,5例生活自理,部分自理和完全不能自理各1例,9例死亡。VEGF基因突变率为75％(18/24),HB中均见VEGF过度表达。结论 CNS-HB病人的手术治疗结果良好,VHL相关病人的远期愈后较差。