Amy A. Pruitt

Assumptions in the radiotherapy of glioblastoma

In the light of advances in computerized tomography (CT), we have retrospectively evaluated the assumptions that underlie the radiation therapy of glioblastoma: (1) No neuroradiologic technique provides an accurate delineation of tumor bulk and location, (2) glioblastoma is commonly multicentric, and (3) a major source of therapeutic failure is recurrence beyond radiotherapy fields. CT scans, performed on glioblastoma patients within 2 months of postmortem examination, defined both gross and microscopic tumor extent (within a 2-cm margin) in all but 6 of 35 patients evaluated. The major source of error was subependymal spread (four patients). Multicentricity occurred in only 4% of untreated and 6% of treated (radiotherapy with or without chemotherapy) patients. All multicentric lesions were identified on CT scans. Serial CT scans on 42 patients revealed that glioblastoma recurred within a 2-cm margin of the primary site in 90%. Occurrences outside this margin were accurately delineated by CT in all instances. Because most patients show recurrence within or in close proximity to the original site, current radiation doses would appear to be inadequate for therapy of the primary tumor. CT scan accuracy may permit smaller-field and higher-dose irradiation therapy for glioblastoma.

Infections of the nervous system.

Epidemiologic trends causing infections of the nervous system remain a significant source of morbidity and mortality one half-century after the introduction of penicillin. This article outlines common causes of bacterial meningitis, aseptic meningitis syndrome, encephalitis, abscess, spinal cord syndromes, and cranial and peripheral nerve problems. Recommendations for diagnostic evaluation and both empiric and definitive antimicrobial therapy are offered; controversial management issues are also discussed. The protean manifestations of varicella-zoster virus and Lyme diseases are outlined. In addition, special considerations in the immunocompromised host, including organ transplant recipients, cancer patients, and HIV-positive persons are explained, and antimicrobial therapy is discussed.

Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis : results from the 15-year analysis of the US prospective open-label study of glatiramer acetate

The ongoing US Glatiramer Acetate (GA) Trial is the longest evaluation of continuous immunomodulatory therapy in relapsing—remitting multiple sclerosis (RRMS). The objective of this study was to evaluate up to 15 years of GA as a sole disease-modifying therapy. Two hundred and thirty-two patients received at least one GA dose since study initiation in 1991 (mITT cohort), and 100 (43%, Ongoing cohort) continued as of February 2008. Patients were evaluated every 6 months using the Expanded Disability Status Scale (EDSS). Mean GA exposures were 8.6 ± 5.2, 4.81 ± 3.69, and 13.6 ± 1.3 years and mean disease durations were 17, 13, and 22 years for mITT, Withdrawn and Ongoing cohorts, respectively. For Ongoing patients, annual relapse rates (ARRs) maintained a decline from 1.12 ± 0.82 at baseline to 0.25 ± 0.34 per year; 57% had stable/improved EDSS scores (change ≤ 0.5 points); 65% had not transitioned to secondary progressive multiple sclerosis (SPMS); 38%, 18%, and 3% reached EDSS 4, 6, and 8. For all patients on GA therapy (the mITT cohort), ARRs declined from 1.18 ± 0.82 to 0.43 ± 0.58 per year; 54% had stable/improved EDSS scores; 75% had not transitioned to SPMS; 39%, 23%, and 5% reached EDSS 4, 6, and 8. In conclusion, multiple sclerosis patients with mean disease duration of 22 years administering GA for up to 15 years had reduced relapse rates, and decreased disability progression and transition to SPMS. There were no long-term safety issues.

A prospective open-label study of glatiramer acetate: Over a decade of continuous use in multiple sclerosis patients

A decade of continuous glatiramer acetate (GA) use by relapsing remitting multiple sclerosis (RRMS) patients was evaluated in this ongoing, prospective study, and the neurological status of ‘Withdrawn’ patients was assessed at a 10-year long-term follow-up (LTFU) visit. Modified intention-to-treat (mITT, n=232) patients received ≥ 1 GA dose since 1991; ‘Ongoing’ patients (n=108) continued in November 2003. Of 124 patients, 50 Withdrawn patients returned for LTFU. Patients were evaluated every six months (EDSS). Mean GA exposure was 6.99, 10.1 and 4.26 years for mITT, Ongoing, and Withdrawn/LTFU patients, respectively. While on GA, mITT relapse rates declined from 1.18/year prestudy to ∼1 relapse/5 years; median time to ≥ 1 EDSS point increase was 8.8 years; mean EDSS change was 0.739±1.66 points; 58% had stable/improved EDSS scores; and 24, 11 and 3% reached EDSS 4, 6 and 8, respectively. For Ongoing patients, EDSS increased 0.509±1.65; 62% were stable/improved; and 24, 8 and 1% reached EDSS 4, 6 and 8, respectively. For Withdrawn patients at 10-year LTFU, EDSS increased 2.249±1.86; 28% were stable/improved; and 68, 50 and 10% reached EDSS 4, 6 and 8, respectively. While on GA nearly all patients (mean disease duration 15 years) remained ambulatory. At LTFU, Withdrawn patients had greater disability than Ongoing patients.

Glatiramer acetate (Copaxone): comparison of continuous versus delayed therapy in a six-year organized multiple sclerosis trial

The aim of this study was to assess the long-term safety and efficacy of glatiramer acetate (GA) for patients with multiple sclerosis (MS) who received active treatment versus those on placebo for approximately 30 months (24-35 months) before receiving GA during a six-year organized, prospective open label study. Entry required two relapses in the previous two years and an Expanded Disability Status Scale (EDSS) score of 0-5. Patients (251) were equally randomized to daily subcutaneous G A, 20 mg, or to placebo. A fter approximately 30 months, 208 patients continued in an open label study: 101 continued on G A and 107 switched from placebo to active drug. Groups were well matched at randomization and entry to the open label study. Patients always on G A showed a steady decline in relapses: a mean of 1.5 per year at entry, a mean of 0.42 over the entire six years (95% C I=0.34-0.51), a 72% reductio n (P =0.0001). They averaged a relapse every four+ years (yearly rate 0.23 in year six) and 26/101 remain relapse free. Patients did less well if on placebo for 30 months, but relapses then declined, and by year six the rates were similar. O f patients always on GA, 69% showed neurological improvement of > 1 EDSS steps or remained stable compared with 57% if G A treatment was delayed. O f relapse-free patients always on G A over six years, only three of 26 (11%) were worse by]-1 EDSS steps, whereas nine of 21 (43%) in the placebo/active group were worse (P B-0.03). Disability, measured every six months, showed that the group of patients always on G A was relatively stable over the six years, while the group who received placebo for the first two-and-a-half years did significantly less well. Daily injections of GA were well tolerated. This longest ever organized MS treatment trial shows that delaying therapy with GA increases the risk of neurologic disability, reinforcing the rationale for using G A as a first-line treatment early in the course of relapsing-remitting MS.

Neurological Complications of Transplantation: Part I: Hematopoietic Cell Transplantation

Hematopoietic cell transplantation (HCT) is the preferred treatment for an expanding range of neoplastic and nonmalignant conditions. Increasing numbers of solid organ transplantations (SOTs) add an additional population of immunosuppressed patients with multiple potential neurological problems. While the spectrum of neurological complications varies with conditioning procedure and hematopoietic cell or solid organ source, major neurological complications occur with all transplantation procedures. This 2 part review emphasizes a practical consultative approach to central and peripheral nervous system problems related to HCT or SOT with clinical and neuroimaging examples from the authors’ institutional experience with the following conditions: the diversity of manifestations of common infections such as varicella zoster virus, Aspergillus, and progressive multifocal leukoencephalopathy (PML), drug therapy-related complications, stroke mechanisms, the spectrum of graft versus host disease (GVHD), and neurologically important syndromes of immune reconstitution inflammatory syndrome (IRIS), posterior reversible encephalopathy syndrome (PRES), and posttransplantation lymphoproliferative disorder (PTLD). These complications preferentially occur at specific intervals after HCT and SOT, and neurological consultants must recognize an extensive spectrum of syndromes in order to effect timely diagnosis and expedite appropriate treatment.

Episodic neurologic dysfunction with migraine and reversible imaging findings after radiation

Reported are three adults who developed frequent episodes of a complex neurologic syndrome years after radiation therapy for a brain tumor. MRI and [18F]fluorodeoxyglucose PET performed during the episodes demonstrated dramatic gyral thickening with enhancement and intense hypermetabolism in symptomatic regions that resolved on follow-up studies. EEG during episodes showed only slowing. The differential diagnosis and imaging findings are reviewed.

Nervous system infections in patients with cancer

The diagnostic approach to the patient with cancer with suspected CNS infection depends on an analysis of the patients immune defect, the time course of development of manifestations of infection, and the type of clinical syndrome with supportive evidence for a specific diagnosis coming from laboratory and neuroradiographic data. Most patients with CNS infections can be grouped into those with signs of meningitis or meningoencephalitis and those with focal mass lesions. A smaller group presents with stroke-like onset. Except for the group with strokes, those with focal deficits usually present in a more indolent fashion, whereas those with meningitis and encephalitis present more acutely [63]. Patients with B-lymphocyte dysfunction are susceptible to encapsulated bacterial pathogens. Patients with T-lymphocyte impairment develop CNS infections that are caused by intracellular pathogens, particularly viruses (HSV, JC, CMV, HHV-6), Nocardia, Aspergillus, and Toxoplasma. Many noninfectious entities, such as drug treatment complications, radiation effects, recurrent tumor, and paraneoplastic syndromes, can mimic CNS infections. Although cryptococcosis, bacterial meningitis, and some viral infections are easily diagnosed from Grams stain, culture, or PCR, patients with mass lesions may require tissue biopsy to confirm diagnosis. Patients with cancer differ from normal hosts in the distribution of pathogens, and there is a wider range of differential diagnostic issues, both infectious and noninfectious, for the relatively few clinical syndromes that present as potential CNS infections.

Analysis of the treatment of neuromyelitis optica

BACKGROUND Treatment options for neuromyelitis optica (NMO) are currently based on small retrospective case series and open label studies, ranging from 10 to 103 patients. OBJECTIVE To compare the efficacy and tolerability of azathioprine, cyclophosphamide, mycophenolate, and rituximab in patients with neuromyelitis optica. METHODS This is a retrospective chart review and telephone follow-up study of 71 patients with NMO or NMO spectrum disorder, 54 of whom were treated with the study drugs. We compared adverse events, annualized relapse rates and expanded disability status scales before and after treatment. RESULTS The median ARR decreased from 1.17 to 0.25 on rituximab (P<0.01), 0.92 to 0.56 on azathioprine (P=0.475), 1.06 to 0.39 on mycophenolate (P<0.05) and 1.30 to 0.92 on cyclophosphamide (P=0.746). When compared directly to azathioprine, rituximab significantly reduced relapse rates (P=0.021). The median EDSS decreased from 7 to 5 on rituximab (P<0.01) and 7 to 6 on azathioprine (P<0.01), and did not change significantly on mycophenolate (4 to 5; P=0.463) or cyclophosphamide (6.5 to 6.5; P=0.881). Twenty-five percent of patients noted adverse events on rituximab, 36% on azathioprine, 36% on mycophenolate, and 80% on cyclophosphamide. CONCLUSION Rituximab significantly reduces relapse rates and improves disability while maintaining comparable tolerability to other immunosuppressive treatments for NMO.

Central nervous system infections in cancer patients.

With improved treatments, patients with many types of cancer survive longer. However, both the acute adverse effects of more intensive therapies and the risks of chronic immunosuppression have led to a diverse and evolving spectrum of central nervous system (CNS) infections. The presentation and course of CNS infections in cancer patients may be different from those in patients without cancer, complicating and delaying accurate diagnosis. New syndromes related both to the underlying malignancies and to their treatment continue to emerge. Noninfectious disorders such as adverse drug effects, vascular lesions, and radiation effects can mimic CNS infections. The two major clinical presentations of CNS infections are meningoencephalitic syndromes and focal deficits due to mass lesions. The range of pathogens can be narrowed by considering the type of immune deficit present, local nosocomial trends, and the specific vulnerabilities created by the underlying disease and treatment regimen. Patients undergoing neurosurgical procedures and those receiving hematopoietic cell transplants (HCT) account for the majority of cancer patients with CNS infections. Significant recent changes reviewed here include evolving patterns of bacterial meningitis, current treatment recommendations for fungal infections, special infectious risks associated with immunomodulatory therapies, and neuroimaging techniques to distinguish infection from other intracranial processes.