Raja B. Khan

Is intrathecal methotrexate necessary in the treatment of primary CNS lymphoma

Systemic high-dose methotrexate (HD-MTX) is the most effective chemotherapeutic agent in the treatment of primary central nervous system lymphoma (PCNSL). Leptomeningeal involvement is common and intrathecal methotrexate (IT-MTX) is frequently used in combination with HD-MTX, but its benefits are not established. Using a case-controlled retrospective study, matching patients treated with HD-MTX with or without IT-MTX, we found no difference in survival, disease control, or neurotoxicity.

A phase II study of extended low-dose temozolomide in recurrent malignant gliomas

Temozolomide is an effective agent in the treatment of recurrent malignant gliomas. The standard dosage is 150-200 mg/m2 per day for 5 days in a 28-day cycle. A prior phase I study established a chronic daily temozolomide dose that significantly increased the total dose administered and suggested a superior response rate. In a prospective phase II trial, we treated 35 patients with recurrent malignant gliomas with temozolomide 75 mg/m2 per day for 42 consecutive days in a 70-day cycle. Median age was 55 years (range, 27-73 years) and median Karnofsky performance score was 70 (range, 60-90). Twenty-eight (79%) patients had glioblastoma multiforme, 3 (9%) anaplastic astrocytoma, 2 (6%) anaplastic oligodendroglioma, and 2 (6%) anaplastic oligoastrocytoma. All but one had prior radiotherapy, and 27 had prior chemotherapy. There were 2 partial (anaplastic astrocytoma) and 3 minor (glioblastoma multiforme) radiographic responses; 17 patients had progressive disease at the end of the first cycle. In 55 cycles of temozolomide, there were 8 episodes of asymptomatic drug-related grade 3 toxicity: 6 lymphopenia, 1 neutropenia, and 1 thrombocytopenia. Median progression-free survival and overall survival were 2.5 and 8.7 months (2.3 and 7.7 months in glioblastoma multiforme patients). At 6 months, progression-free survival and overall survival rates were 27% and 67% (19% and 60% in glioblastoma multiforme). Quality of life scores did not change significantly during treatment. We conclude that the extended low-dose schedule of temozolomide is well tolerated in heavily pre-treated patients; however, our results do not support an improved rate of response or survival.

Use of diffusion weighted magnetic resonance imaging in predicting early postoperative outcome of new neurological deficits after brain tumor resection.

OBJECTIVEnTo study risk factors for the development of postoperative neurological deficits after brain tumor resection and to define prognostic factors for recovery.nnnMETHODSnWe prospectively studied 82 brain tumor patients undergoing tumor resection. Pre- and postoperative neurological examination, functional and performance status, cancer treatment, cardiovascular risk factors, seizure history, and blood pressure and oxygen saturation were recorded perioperatively. Postoperative magnetic resonance imaging scans were obtained within 72 hours of surgery, and the radiologist was blinded to the patients status. Abnormalities on magnetic resonance diffusion weighted images were classified as new if they extended beyond the tumor cavity margins and were absent before surgery.nnnRESULTSnOf the 80 assessable patients, 24 had a new or increased postoperative deficit by at least one point on the National Institutes of Health Stroke Scale. Presence of preoperative neurological deficits predicted development of postoperative deficits, whereas a new diffusion weighted imaging lesion after craniotomy predicted incomplete recovery of a new postoperative deficit.nnnCONCLUSIONnPostoperative diffusion magnetic resonance imaging is useful in predicting early functional recovery from new deficits after brain tumor surgery.

HTLV-1 and its neurological complications.

BACKGROUND—Since its discovery in 1980, human T-cell lymphotropic virus type-1 (HTLV-1) has been associated with a number of neurological diseases. The distribution of HTLV-1-associated neurological disease is worldwide. In endemic areas, up to 30% of the population may be infected with HTLV-1; however, only a small percentage of infected persons develops neurological disease. REVIEW SUMMARY—In 1986, HTLV-1 infection was reported in patients of chronic progressive myelopathy of uncertain etiology, and the disease entity was called HTLV-1-associated myelopathy/tropical spastic paraparesis. Recently, HTLV-1 infection has been associated with polymyositis and uveitis. Interestingly, a single patient may display more than one syndrome. Although other neurological syndromes occur in HTLV-1-infected individuals, there is not enough epidemiologic data that show a strong association. Treatment of HTLV-1-associated neurological disease is challenging, and well-controlled studies are lacking. CONCLUSION—As neurologists and other scientists begin to understand the pathophysiology of HTLV-1 infection, improved therapies should be developed. Randomized trials with longer follow-up are required to understand the effect of treatment on disability and quality of life.

Leptomeningeal metastasis from an intracranial epidermoid cyst.

Epidermoid tumors are benign and constitute 1% of all intracranial tumors. Squamous cell carcinoma (SCC) arising in an epidermoid is rare, and leptomeningeal metastasis (LM) from malignant degeneration of an epidermoid is even less common; we have identified only three such patients in the literature.1-3⇓⇓nnDemonstration of cancer cells in the CSF is the diagnostic “gold standard” for LM. Sensitivity of a single test is 50 to 60%, but improves to 85% with repeated testing.4 Typical findings on MRI scan can establish the diagnosis of LM without CSF cytology, but only in patients with a known cancer. CSF tumor marker analysis may improve diagnostic sensitivity.5,6⇓ We report a patient who developed LM from malignant degeneration of an epidermoid cyst, had elevated CSF tumor markers, and had persistently negative CSF cytology.nnA 53-year-old man presented in October 1998 with facial spasms. His neurologic examination was normal. Brain MRI scanning revealed a nonenhancing, cystic mass anterior to the …

Rapid growth of a basilar aneurysm.

We describe a patient who developed, over a 22-month period, a giant aneurysm of his basilar artery. A prior MRI of the brain done for nonspecific symptoms showed a normal brainstem and basilar artery. At presentation, he had a repeat MRI scan for a 4-month history of a partial right oculomotor nerve palsy and left hemiparesis. The MRI revealed a giant aneurysm of the top of the basilar artery. This was treated by angiographic placement of Guglielmi detachable coils (GDC) after surgical intervention was deemed unfeasible. This case illustrates the acquired nature of intracranial aneurysms. All inoperable intracranial aneurysms should be closely monitored and MRI and MR angiography may currently be the best noninvasive methods for this purpose. Intra-arterial GDC embolization of aneurysms is an alternative treatment when surgery is not possible.

Long-Term Outcomes Among Survivors of Childhood Central Nervous System Malignancies: Late Mortality, Subsequent Neoplasms, Endocrine and Neurologic Morbidity

According to the most recent estimates from the Surveillance, Epidemiology and End Results (SEER), 74% of children younger than 20 years of age diagnosed with a central nervous system (CNS) malignancy will become 5-year survivors (Howlader et al. 2012). Current therapy for children with CNS malignancies often includes both surgical resection and a combination of CNS-directed radiation therapy (RT) and chemotherapy. Among survivors of all primary pediatric cancers, survivors of CNS malignancies are at the highest risk for late mortality (Mertens et al. 2001; Taylor and Potish 1985; Dama et al. 2006). Furthermore, survivors of CNS malignancies are at risk for developing subsequent neoplasms and chronic endocrine and neurologic conditions (Neglia et al. 2001; Broniscer et al. 2004; Cardous-Ubbink et al. 2007; Duffner et al. 1998; Devarahally et al. 2003; Peterson et al. 2006; Jenkinson et al. 2004; Hammal et al. 2005; Oeffinger et al. 2006; Packer et al. 2003; Gurney et al. 2003a). Documenting the incidence of and risk factors for these conditions in the second, third, and fourth decades of survival in this aging population is essential as future efforts to reduce late morbidity and mortality through modification and risk stratification of primary therapy, screening and early detection of late effects, and interventions to reduce risk and impact of late effects are dependent on identifying populations at highest risk for poor outcomes. Thus, while 5-year survival has improved, the patterns of late morbidity and mortality after exposure to multimodal therapy are only now being established as this population ages. Future studies will need to identify whether exposure to modern therapies (including focal RT for embryonal CNS tumors in infants, whole ventricular volume RT for germ cell tumors, targeted therapies, and immunotherapy, among others) increases or decreases the risk of long-term morbidity and late mortality compared with patients treated in previous eras (Armstrong et al. 2009a).

Attainment of Functional and Social Independence in Adult Survivors of Pediatric CNS Tumors: A Report From the St Jude Lifetime Cohort Study

Purpose Beyond survival, achieving independence is a primary goal for adult survivors of pediatric CNS tumors. However, the prevalence of and risk factors for failure to achieve independence, assessed with multiple concurrent indicators, have not been examined. Patients and Methods Functional and social independence was assessed in 306 survivors (astrocytoma [n = 130], medulloblastoma [n = 77], ependymoma [n = 36], and other [n = 63]; median current age, 25.3 years [range, 18.9 to 53.1 years]; time since diagnosis, 16.8 years [range, 10.6 to 41.8 years]). Six observed indicators were used to identify latent classes of independence, which included employment, living independently, assistance with personal care, assistance with routine needs, obtaining a drivers license, and marital status. Physical performance impairments were defined as scores < 10th percentile on measures of aerobic capacity, strength, flexibility, balance, mobility, and adaptive function. Multinomial logistic regression estimated odds ratios (ORs) and 95% CIs were calculated for associations of disease/treatment exposures and impairments in physical performance with nonindependence. Results Three classes of independence were identified as independent (40%), moderately independent (34%), and nonindependent (26%). In multivariable models, craniospinal irradiation (OR, 4.20; 95% CI, 1.69 to 10.44) and younger age at diagnosis (OR, 1.24; 95% CI, 1.14 to 1.35) were associated with risk of nonindependence versus independence. Beyond impaired IQ, limitations in aerobic capacity (OR, 5.47; 95% CI, 1.78 to 16.76), flexibility (OR, 3.66; 95% CI, 1.11 to 12.03), and adaptive physical function (OR, 11.54; 95% CI, 3.57 to 37.27) were associated with nonindependence versus independence. Nonindependent survivors reported reduced physical but not mental health-related quality of life compared with independent survivors. Conclusion Sixty percent of survivors of pediatric CNS tumors do not achieve complete independence as adults. Reduction in intensity of primary therapies and interventions that target physical performance and adaptive deficits may help survivors to achieve greater independence.

The Complex Diagnostic Challenge in Children With Non–Central Nervous System Cancer and Cerebellar Mutism

Multiple etiologies should be considered in the differential diagnosis of immunocompromised patients with non–central nervous system cancer and viral infections who develop mutism. Acute cerebellitis, caused by infections or by neurotoxicity resulting from chemotherapy; paraneoplastic cerebellar degeneration; atypical posterior reversible encephalopathy syndrome; and acute disseminated encephalomyelitis may all cause mutism in such patients. This condition warrants prompt recognition and may require treatment with immunotherapy, as it may be an immune-mediated process. We present 2 patients with leukemia and viral illness who developed cerebellar mutism in the setting of acute cerebellitis and responded to immunotherapy, suggesting that the condition involved a parainfectious immune-mediated response.