Headache types, related morbidity, and quality of life in survivors of childhood acute lymphoblastic leukemia: a prospective cross sectional study.

BACKGROUND: Increased headache prevalence was recently reported in survivors of childhood ALL. Headache sub types, related morbidity, and effect on quality of life has not been reported thus far. OBJECTIVE: To study headache prevalence and type, related disability, and quality of life in a cohort of childhood acute lymphoblastic leukemia (ALL) survivors. METHODS: Childhood ALL survivors in at least 1-year of remission and 5 years from diagnosis completed questionnaires and were evaluated by a neurologist. Disability was evaluated with Pediatric Migraine Disability Assessment scale and the Short Form-36 Health Survey assessed quality of life. RESULTS: Thirty nine of 72 (54%) females and 37 of 90 (41%) males reported headaches. Median time from ALL diagnosis to first headache was 5.2 years and median age at headache onset was 10.1 years in 76 participants with headache. Migraine headaches were diagnosed in 51 (31%) and episodic tension-type headaches in 49 (30%); migraine and tension-type headaches co-existed in 24 (15%) and 18 (11%) participants had chronic daily headaches. Fatigue was associated with migraine headache while hypertension and female gender associated with tension type headache. Headache-related disability was mild in 22 (29%), moderate in 7 (9%), and severe in 5 (7%) survivors, and was absent in the remaining 42 (55%) survivors with headache. Both migraine and tension type headaches associated with reduced mental component scores, while headache related disability associated with a reduced physical component scores. CONCLUSIONS: Headaches are common in ALL survivors but only a minority has significant disability or impairment of quality of life.

Neurologic morbidity and quality of life in survivors of childhood acute lymphoblastic leukemia: a prospective cross-sectional study.

PURPOSE: Childhood acute lymphoblastic leukemia (ALL) is treated with potentially neurotoxic drugs and neurologic complications in long-term survivors are inadequately studied. This study investigated neurologic morbidity and its effect on quality of life in long-term survivors of childhood ALL. METHODS: Prospective, single institution, cross-sectional, institutional review board-approved study of long-term ALL survivors. Participants were recruited from institutional clinics. Participants answered an investigator-administered questionnaire followed by evaluation by a neurologist. Quality of life (QOL) was also assessed. RESULTS: Of the 162 participants recruited over a 3-year period, 83.3% reported at least one neurologic symptom of interest, 16.7% had single symptom, 11.1% had two symptoms, and 55.6% had three or more symptoms. Symptoms were mild and disability was low in the majority of participants with neurologic symptoms. Median age at ALL diagnosis was 3.9 years (0.4-18.6), median age at study enrollment was 15.7 years (6.9-28.9), and median time from completion of ALL therapy was 7.4 years (1.9-20.3). On multivariable analyses, female sex correlated with presence of dizziness, urinary incontinence, constipation, and neuropathy; use of ≥10 doses of triple intrathecal chemotherapy correlated with urinary incontinence, back pain, and neuropathy; cranial radiation with ataxia; history of ALL relapse with fatigue; and CNS leukemia at diagnosis with seizures. Decline in mental QOL was associated with migraine and tension type headaches, while physical QOL was impaired by presence of dizziness and falls. Overall, good QOL and physical function was maintained by a majority of participants. CONCLUSIONS: Neurologic symptoms were present in 83% long-term ALL survivors. Symptoms related morbidity and QOL impairment is low in majority of survivors. Female sex, ≥10 doses of intrathecal chemotherapy, and history of ALL relapse predispose to impaired QOL. IMPLICATIONS FOR CANCER SURVIVORS: This study will educate survivors and their care providers regarding cancer or treatment-related neurologic symptoms and morbidity. This study will help them understand factors contributing to impaired QOL when present.

Long-term outcome and risk factors for uncontrolled seizures after a first seizure in children with hematological malignancies.

Long-term outcomes of seizures that develop during treatment of childhood hematological malignancies have not been described. We analyzed seizure outcome in 62 children with leukemia or lymphoma treated at our institution. There was a median follow-up of 6.5 years since first seizure. Seizure etiology included intrathecal or systemic methotrexate in 24, leucoencephalopathy in 11, brain hemorrhage or thrombosis in 11, meningitis in 4, and no identifiable cause in 12. Seizures remained uncontrolled in 18, and risk factors for poor control included female sex (P = .02), no seizure control with first antiseizure drug (P = .08), and longer interval between cancer diagnosis and seizure onset (P = .09). Poor seizure control after initial antiseizure drug also predicted recurrent seizure after drug withdrawal (P = .04). In conclusion, seizures are controlled with medications in a majority of patients with hematological cancer. After a period without seizures, antiseizure drug withdrawal in appropriately selected patient has a high success rate.

Headaches in children with craniopharyngioma.

Craniopharyngioma frequently involves intracranial pain-sensitive structures. We retrospectively studied prevalence, associated risk factors, and outcome of headaches in children with craniopharyngioma. Fisher exact test and multivariate analysis were used to study association of study variables. Of the 51 craniopharyngioma patients treated at our institution from January 1994 to December 2005, 40 (78%) reported headaches (35 [68%] before tumor diagnosis). Migraine headaches were diagnosed in 32 (63%) and tension-type headaches in 11 patients (22%). The median follow-up period was 2.7 years. At the last follow-up, 38 (75%) were headache free. Presence of hydrocephalus, distortion of circle of Willis, and large tumor volume were associated with headache, and the last 2 variables were also associated with more severe and frequent headaches. Radiation treatment and insertion of Ommaya reservoir were associated with reduced headache frequency. In conclusion, headaches are common in patients with craniopharyngioma and are likely related to tumor size and volume. In most patients, headaches improve with successful tumor treatment.

Symptoms of attention-deficit/hyperactivity disorder in long-term survivors of childhood leukemia.

BACKGROUND: Survivors of childhood acute lymphoblastic leukemia (ALL) sometimes have clinical features that suggest attention-deficit/hyperactivity disorder (ADHD), though few studies have examined specific symptoms in survivors. PROCEDURE: Long-term survivors of childhood ALL (n = 161) received a neurological examination, while parents completed rating scales to establish formal criteria for ADHD. Symptom profiles were generated and compared across demographic and treatment characteristics, as well as medical tests associated with brain pathology. RESULTS: Prevalence rates of ADHD were similar in survivors (10.5%) compared to those reported in the general population (7-10%). However, 25.5% of survivors reported symptoms that impair functioning in multiple settings, with attention problems being most common. These symptoms were associated with cranial radiation therapy (CRT) (mean inattentive symptoms [SD] = 3.6 [3.19] for group treated with CRT vs. 1.6 [2.40] for non-CRT group, P = 0.0006), and survivors who demonstrated impaired anti-saccades during the neurologic exam (mean inattentive symptoms [SD] = 3.4 [3.29] for those with impaired anti-saccades vs. 1.4 [2.41] for those with normal anti-saccades; P = 0.0004). CONCLUSIONS: The presence of a neurologically-based phenotype of attention problems in survivors of leukemia that is not fully captured by the syndrome of ADHD suggests that treatments specific to childhood ALL should be explored.

Levetiracetam as monotherapy for seizures in a neonate with acute lymphoblastic leukemia.

Congenital acute lymphoblastic leukemia (ALL) is a relatively rare disorder that is characterized by frequent central nervous system involvement that may increase the risk for seizures. Appropriate choice of anticonvulsant therapy with respect to ongoing oncologic treatment is not established in this age group. We report the case of a neonate with ALL who was successfully treated for seizures with levetiracetam monotherapy. This full-term boy did well until 3 days of age when he had an episode of left extremity jerking (07/06/07). Computed tomography of the head demonstrated extensive multifocal intraparenchymal hemorrhages. Initial EEG demonstrated multifocal epileptiform activity. Patient was loaded with Phenobarbital at 20 mg/kg. Complete blood count revealed leukocytosis (78 x 103/mm(3)). Peripheral blood smear contained blastocytes and DNA analysis confirmed B-cell ALL. A second focal seizure was reported on the same day and he was re-loaded with Phenobarbital. Maintenance dosing of Phenobarbital was initiated and no further seizures were noted. A repeat EEG on 7/10/07 remained abnormal with excessive multifocal sharp waves. Continuation of anticonvulsant therapy was recommended. Given concern for interaction between Phenobarbital and planned chemotherapy regimen, oncology requested a non-enzyme inducing anticonvulsant. Phenobarbital was subsequently weaned and Levetiracetam monotherapy initiated at 40 mg/kg/day (07/10/2007). Currently, the patient is seizure free at 8 months of age on Levetiracetam monotherapy. The use of Levetiracetam as monotherapy in neonates has not been formally evaluated and experience is limited. We report the successful use of levetiracetam monotherapy after Phenobarbital load in a neonate with leukemia and localization-related epilepsy.

Leucoencephalopathy, transverse myelopathy, and peripheral neuropathy in association with glutamic acid decarboxylase-65 (GAD) antibodies in children with cancer.

Neurologic toxicity may occur as a direct effect of cancer and its therapy or indirectly because of a dysfunctional immune system. The authors report the development of axonal neuropathy, myelopathy, and leucoencephalopathy associated with glutamic acid decarboxylase-65 (GAD) antibodies in 4 children with progressive cancer who were heavily pretreated. Three patients with refractory leukemia and 1 with Ewing sarcoma developed paraplegia with sensory level and dorsal column dysfunction. Three developed leucoencephalopathy and 1 died of neurologic disease. All had high serum titers of GAD antibodies during the progressive phase of the illness, and the antibody levels returned to normal with the stability of the neurologic disease. Three survivors are showing gradual recovery. This syndrome of central and peripheral nervous system toxicity may have resulted from chemotherapy toxicity or from immune dysfunction, as suggested by the high GAD antibody titers.

Temozolomide after radiotherapy for newly diagnosed high-grade glioma and unfavorable low-grade glioma in children.

Chemotherapy is commonly used in the treatment of children with high-grade glioma, although its usefulness is uncertain. We conducted a multi-institutional study to evaluate the efficacy of temozolomide given after radiotherapy in children with newly diagnosed high-grade glioma and unfavorable low-grade glioma (gliomatosis cerebri or bithalamic involvement). Optional window therapy of intravenous irinotecan (10 doses of 20 mg/m2 per cycle x 2) was given over 6 weeks. The 5-day schedule of temozolomide (200 mg/m2 per day) started 4 weeks after the completion of radiotherapy and continued for a total of 6 cycles. Thirty-one eligible patients (median age: 12.3 years) participated. Tumors most commonly involved cerebral hemispheres (n = 13, 42%) and thalamus (n = 14, 45%). Whereas six patients underwent radical resection, the remainder had limited surgery, including biopsy (n = 14, 45%). The predominant histologic diagnoses were glioblastoma multiforme (n = 15, 48%) and anaplastic astrocytoma (n = 10, 32%). Two patients had bithalamic grade II astrocytoma. Twenty-seven patients received radiotherapy (median dose: 59.4 Gy), including craniospinal irradiation in 3 because of leptomeningeal spread. Four patients did not receive radiotherapy in this study because of consent withdrawn (n = 2), toxicity during window therapy (n = 1), or at the physician's discretion (n = 1). Twenty-three patients received 112 cycles of temozolomide therapy. The 2-year progression-free and overall survival estimates were 11 +/- 5% and 21 +/- 7%, respectively. Although the heterogeneity of prognostic factors in our patients made assessment of treatment outcome more difficult, the addition of 6 cycles of temozolomide after radiotherapy did not seem to alter the poor outcome of these patients.