Investigation of germline PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 alterations in familial glioma.

Epidemiological studies suggest that some familial aggregations of glioma may be due to inherited predisposition. Many genes involved in familial cancers are frequently altered in the corresponding sporadic forms. We have investigated several genes known to be altered in sporadic gliomas for their potential contribution to familial glioma. Fifteen glioma patients with a family history of brain tumors were identified through the Mayo Clinic Department of Neurology (nine diffuse astrocytomas, two oligodendrogliomas, two mixed oligoastrocytomas, one pilocytic astrocytoma, and one pineal glioma). Eleven of the propositi had one or more first degree relative with a glioma. Lymphocyte DNA was derived from each of the patients and analyzed by polymerase chain reaction (PCR) and direct sequencing of the PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 genes. In addition, fluorescence in situ hybridization (FISH) was performed on EBV-transformed lymphocytes from each affected individual to detect germline copy number of the p16(INK4A)/p14(ARF) tumor suppressor region. A p53 germline point mutation was identified in one family with some findings of Li-Fraumeni syndrome, and a hemizygous germline deletion of the p16(INK4A)/p14(ARF) tumor suppressor region was demonstrated by FISH in a family with history of both astrocytoma and melanoma. Thus, whereas germ-line mutations of PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 are not common events in familial glioma, outside of familial cancer syndromes, point mutations of p53 and hemizygous deletions and other rearrangements of the p16(INK4A)/p14(ARF) tumor suppressor region may account for a subset of familial glioma cases. Collectively, these data lend genetic support to the heritable nature of some cases of glioma.

Detection of p16, RB, CDK4, and p53 gene deletion and amplification by fluorescence in situ hybridization in 96 gliomas.

Inactivation of the p53 gene is a common early event of astrocytoma tumorigenesis. Alternatively, since the p16, retinoblastoma (RB), and CDK4 genes have been implicated in malignant progression, detection of losses or amplifications of these genes in gliomas could be diagnostically, prognostically, and therapeutically important. We obtained smear preparations from 96 diffuse gliomas and 10 nonneoplastic specimens. Dual-color fluorescence in situ hybridizations using paired probes for CEN9/p16, CEN8/RB, CEN17/p53, and CEN12/CDK4 were performed and revealed expected frequencies of abnormalities, except for p53 losses, which were low (7%). The latter supports the concept that p53 inactivation usually occurs by mitotic recombination. Detected abnormalities of the p16/RB/CDK4 pathway were highly associated with astrocytic differentiation and were univariately associated with decreased patient survival. However, only patient age and histologic classification retained statistical significance on multivariate analysis. We conclude that in diffuse gliomas, p16/RB/CDK4 abnormalities are markers of astrocytic phenotype. Thus, their detection by fluorescence in situ hybridization may have diagnostic usefulness in cases with equivocal morphologic features. Although our numbers are small, we find no additional prognostic significance to these genetic abnormalities one age, grade, and oligodendroglial histology are taken into account.

Clinicopathologic study of 85 similarly treated patients with anaplastic astrocytic tumors. An analysis of DNA content (ploidy), cellular proliferation, and p53 expression.

BACKGROUND: The biologic behavior of anaplastic (World Health Organization Grade III) astrocytomas and oligoastrocytomas is highly variable, ranging from rapid progression to prolonged survival. It is difficult to predict the outcome of an individual patient based on morphology alone. METHODS: To determine the prognostic value of commonly used clinicopathologic markers, we reviewed our experience with 85 similarly treated patients enrolled in 3 North Central Cancer Treatment Group high grade glioma protocols. The pathology was comprised exclusively of primary anaplastic astrocytic tumors (66 astrocytomas and 19 oligoastrocytomas). Variables examined included patient age, morphologic type, preoperative performance score, extent of surgery, solitary versus multiple mitoses, DNA flow cytometric and image morphometric parameters, and expression of proliferating cell nuclear antigen, MIB-1, and p53 expression. RESULTS: The study was comprised of 48 men and 37 women ranging in age from 14-79 years (median age, 47 years). Overall survival ranged from <1 month to >12 years (median, 21.6 months). Statistical analyses revealed that age accounted for the majority of this extensive variability in survival. The median survival times were 65. 5 months, 22.1 months, and 4.4 months, respectively, for the groups <40 years, 40-59 years, and >/=60 years, respectively (P < 0.0001). On univariate analyses, aneuploidy by flow cytometry and a low performance score also predicted a better survival (P values of 0.04 and 0.009, respectively). Statistical trends predicting a better survival were observed for patients with a solitary mitosis and p53 immunopositivity. However, only patient age remained significant in multivariate models. CONCLUSIONS: In a small but relatively uniformly treated cohort of patients with anaplastic astrocytomas and oligoastrocytomas, patient age was associated strongly and inversely with overall survival. Once patient age was taken into account, the clinical and pathologic markers tested appeared to be of limited prognostic value.

Tumor suppressor gene alterations in malignant gliomas: histopathological associations and prognostic evaluation.

We have examined a series of 135 gliomas for alterations of the p53, CDKN2A (p16) and PTEN tumor suppressor genes (TSGs) in order to evaluate the incidence of their inactivation as a function of tumor malignancy and cellular differentiation, and to examine potential associations with patient outcome. The composition of this series, classified using WHO criteria, is as follows: 27 grade 2 tumors (11 astrocytomas, 12 oligoastrocytomas, 4 oligodendrogliomas), 42 grade 3 tumors (22 astrocytomas, 16 oligoastrocytomas, 4 oligodendrogliomas), and 66 grade 4 tumors (63 astrocytomas and 3 oligoastrocytomas). Similar frequencies of p53 mutation were observed among grade 2 (37.0%), and grade 3 tumors (38.1%), as well as between astrocytomas and mixed tumors. CDKN2A and PTEN mutations were clearly associated with increasing tumor malignancy (occurring in 0% of grade 2 tumors, 14.3% and 4.8% respectively of grade 3 tumors, and 27.3% and 30.3% respectively of grade 4 tumors) and were observed at substantially higher rates among astrocytomas. For the tumor suppressor genes examined, there was no relationship between the occurrence of any two TSG inactivation events. With regard to outcome, the p53 genetic status showed no significant relationship with patient survival. The CDKN2 and PTEN alterations were negative prognostic indicators of survival when evaluated in all 135 gliomas, but failed to predict outcome when evaluated in either of the high grade (3 or 4) tumor groups.

Phase II trial of primary chemotherapy followed by reduced-dose radiation for CNS germ cell tumors.

PURPOSE: A prospective phase II study was initiated to assess the response rate, survival, and late effects of treatment in patients with newly diagnosed CNS germ cell tumors (GCT), using etoposide plus cisplatin followed by radiation therapy prescribed by extent of disease, histology, and response to chemotherapy. PATIENTS AND METHODS: Seventeen patients aged 8 to 24 years with histologically proven CNS GCT received etoposide (100 mg/m2/d) plus cisplatin (20 mg/m2/d) daily for 5 days every 3 weeks for four cycles, followed by radiation therapy. Nine patients had germinomas; eight had mixed GCT. Four patients (three with germinomas and one with mixed GCT) presented with leptomeningeal dissemination. RESULTS: Radiographically, 14 of 17 patients were assessable for response; 11 patients experienced complete regression, and three had major partial regression before radiation. Six of seven assessable patients with elevated CSF levels of alpha-fetoprotein or betahuman chorionic gonadotropin had normalization with chemotherapy alone; all normalized with combined chemotherapy and radiation therapy. All 17 patients are alive without evidence of disease (median follow-up, 51 months). One patient developed a relapse in the spinal leptomeninges and was rendered free of disease with spinal radiation more than 5 years ago. One patient developed carotid stenosis requiring surgery. Thus far, only minimal long-term deterioration in neurocognitive function has been detected as a consequence of protocol treatment. CONCLUSION: Conventional-dose intravenous chemotherapy with etoposide and cisplatin can effect tumor regression in a high proportion of patients with CNS GCT, including those with leptomeningeal metastases. Acute and long-term toxicities are acceptable. Progression-free survival and overall survival are excellent.

The natural history of asymptomatic meningiomas in Olmsted County, Minnesota.

To define the natural history of asymptomatic meningioma found incidentally on a neuroimaging study, we performed a retrospective analysis of 35 such patients. There were 32 women and three men, with a mean age of 67 years and a mean follow-up of 74 months. Four tumors had progressed on subsequent imaging, and one patient developed symptoms related to the meningioma. Noncalcified tumors were more likely to progress than calcified tumors.

Paraneoplastic encephalomyelitis and seminoma: importance of testicular ultrasonography.

We report two patients with paraneoplastic limbic and brainstem encephalitis associated with occult nonmetastatic testicular seminoma. In each patient, the neoplasm was detectable only by testicular ultrasonography. Male patients with this syndrome in whom lung cancer is not found should undergo testicular ultrasonography as part of the search for an extrapulmonary neoplasm. A normal clinical testicular examination is insufficient to exclude an occult seminoma.

Outcome of peroneal neuropathies in patients with systemic malignant disease.

BACKGROUND: Peroneal neuropathies in patients with systemic cancer previously have been attributed to weight loss, but to the authors' knowledge other associated conditions have not been assessed, and the outcome of peroneal neuropathies in cancer patients has not been studied. METHODS: A retrospective chart review of patients evaluated at the Mayo Clinic between 1984 and 1993 with systemic malignant disease and a clinical diagnosis of peroneal neuropathy was performed to define factors associated with peroneal neuropathies and to assess outcome. All patients underwent neurologic examination and electromyography. RESULTS: Fifty-eight patients with systemic malignant disease were found to have a peroneal neuropathy. Peroneal neuropathies occurred more often in men (45 patients) than in women (13 patients). The median age of the patients was 70 years. The most common cancers were hematologic (12 patients) and pulmonary (11 patients), followed by tumors of the prostate (8 patients), gastrointestinal tract (7 patients), transitional cell (5 patients), breast (5 patients), and colon (5 patients), as well as sarcomas and melanoma (5 patients). The median time to the diagnosis of peroneal neuropathy after the diagnosis of cancer was 5 months. At the time of diagnosis, 34 patients had severe deficits, 19 had moderate deficits, and 5 had mild deficits. Associated factors included weight loss (occurring in 60% of patients), leg crossing (35% of patients), recent chemotherapy (16% of patients), cutaneous vasculitis (5% of patients), and local metastatic lesions (3% of patients). In nearly 50% of patients, peroneal neuropathy improved (25.9%) or resolved (22.4%). In 39.7% of patients, follow-up was inadequate because death occurred soon after diagnosis. Of the patients with adequate follow-up before death, 80% had either improvement (42.9%) or resolution (37.1%). CONCLUSIONS: For those patients with systemic malignant disease in whom peroneal neuropathy develops, the outcome of the neuropathy is good, with the majority of patients achieving partial or complete resolution.

Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors.

Joint predisposition to malignant melanoma and nervous system tumors (NSTs) is a puzzle. Several melanoma susceptibility genes have been identified, including p16, a clustered tumor suppressor. However, the molecular bases of inherited proclivity to NSTs in the absence of a recognizable genetic syndrome are unknown. We analyzed two families with joint proneness to melanoma and NSTs in view of genetic linkage and identification of the causal molecular lesions. Highly informative linkage markers were used for segregation analyses of the predisposition alleles in the two pedigrees. Characterization of the molecular lesions required hemizygosity mapping based on microsatellite markers physically mapped to contigs of the 9p21 region and a Southern blot approach using several PCR-generated probes. Both families were found to be allelic and linked to p16 markers. In the family segregating the melanoma/NST syndrome, a large germ-line deletion ablated the whole p16, p19, and p15 gene cluster (or INK4 locus), whereas a more circumscribed molecular lesion disrupting p16 and p19 but leaving p15 unaltered segregated with the melanoma-astrocytoma syndrome (MIM 155755). Our results suggest that multiple cancer susceptibility in these two families ensues from contiguous tumor suppressor gene deletion. Indeed, known phenotypes associated with germ-line p16 mutations and an apparent correlation between the deletion span and tumor spectrum in the two families suggest a new model of cancer pathogenesis based on the inactivation of contiguous tumor suppressor genes, an alternative to the established pleiotropic effects of single-gene disruption.

Management of recurrent meningeal hemangiopericytoma.

BACKGROUND: Meningeal hemangiopericytoma is an uncommon neoplasm with a high propensity for recurrence. The purpose of this study was to analyze the efficacy of different treatment options in patients with recurrent disease. METHODS: The records of all patients with recurrent meningeal hemangiopericytoma treated at the study institution between 1976 and 1996 were reviewed. RESULTS: Thirty-four consecutive patients were studied. The mainstay of treatment was brain surgery in 21 patients (62%); the median time to recurrence from surgery was 12 months. Ten patients (29%) had 20 recurrent central nervous system (CNS) lesions treated by stereotactic radiosurgery. Of these, 3 previously nonirradiated patients (all with lesion size < 25 mm) achieved a complete response, which persisted at a median of 3 years. In 14 lesions (70%) a partial response (PR) occurred with a median duration of 12 months, whereas 3 lesions (15%) remained stable. Two patients with inoperable CNS lesions received external beam radiation therapy and both had PRs lasting 14 and 24 months, respectively. Nine patients (26%) received radiation therapy for metastatic disease. Of these, seven patients remained stable with good symptomatic relief, and two patients experienced tumor progression. Chemotherapy with doxorubicin-containing regimens was administered in 7 patients (21%); there was only 1 PR that lasted 8 months. The median survival from first recurrence was 4.6 years. CONCLUSIONS: Surgical management is important for the successful treatment of patients with recurrent meningeal hemangiopericytoma. Radiosurgery plays a definite role in the treatment of smaller recurrent CNS lesions. Radiation therapy is helpful in the management of inoperable tumors. More effective chemotherapeutic agents are needed.

Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies.

Type 1 antineuronal nuclear autoantibody (ANNA-1, also known as "anti-Hu") is a marker of neurologic autoimmunity that is highly associated with small-cell lung carcinoma (SCLC). To determine the spectrum of symptoms and signs as well as the frequency of cancer in adult patients who are seropositive for ANNA-1, we reviewed 162 sequential patients (67% female) identified as ANNA-1-positive in a comprehensive immunofluorescence screening test. In 21% of these patients, the antibody test requested by the physician was not ANNA-1. By the end of the follow-up period, cancer had been found in 142 patients (88%). Ten of these lacked evidence of SCLC (4 had prostate carcinoma, 3 breast carcinoma, 1 both prostate carcinoma and melanoma, 1 lymphoma, and 1 squamous-cell lung carcinoma). Of the 132 patients (81%) with proven SCLC, 17 had one or more coexisting malignant neoplasms (6 had renal carcinoma, 4 another lung primary carcinoma, 3 prostate carcinoma, 3 breast carcinoma, and 4 assorted neoplasms). The diagnosis of SCLC in 128 patients (97%) followed the onset of paraneoplastic symptoms. SCLC was identified in 10 patients by chest MRI after an equivocal chest radiograph or CT; in 28 by bronchoscopy, mediastinoscopy, or thoracotomy; and in 7 at autopsy. Neurologic signs in decreasing frequency were neuropathy (sensory > mixed somatic > autonomic > cranial [especially cranial nerve VIII] > motor), cerebellar ataxia, limbic encephalitis, polyradiculopathy, associated Lambert-Eaton myasthenic syndrome, myopathy, myelopathy, opsoclonus/myoclonus, motor neuronopathy, brachial plexopathy, and aphasia. Nineteen patients had a solely gastrointestinal initial presentation, including gastroparesis, pseudo-obstruction, esophageal achalasia, or other dysmotility. We conclude that seropositivity for ANNA-1 can expedite the diagnosis and treatment of otherwise occult cancer in patients, especially tobacco abusers, with varied neurologic and gastroenterologic presentations. The search for SCLC should not end on discovering a different neoplasm.

5-Fluorouracil and levamisole exacerbate demyelination in susceptible mice infected with Theiler's virus.

A multifocal inflammatory leukoencephalopathy is associated with the administration of 5-fluorouracil (5-FU), a pyrimidine analogue, and levamisole (LE), an immunomodulator, in patients receiving adjuvant therapy for colon cancer. Cerebral biopsy demonstrated features indistinguishable from multiple sclerosis. We tested whether administration of these agents directly resulted in inflammatory demyelination in mice or whether they exacerbated demyelination in a host predisposed to myelin injury. We used mice intracerebrally infected with Theiler's murine encephalomyelitis virus (TMEV) which serves as an excellent model for multiple sclerosis. Varying dosages of 5-FU (240 micrograms-2.4 mg) and LE (40 micrograms-1 mg) were administered alone or in combination on a fixed schedule to 52 normal SJL mice and 61 Theiler's virus-infected mice (51 SJL/J mice susceptible to demyelination; 10 C57BL10 mice resistant to demyelination). Controls included 6 noninfected SJL and 26 infected mice (16 susceptible; 10 resistant) treated with phosphate-buffered saline (PBS). Inflammation or demyelination was not detected in brains or spinal cords of noninfected SJL mice treated with 5-FU and/or LE. TMEV-susceptible SJL mice treated with LE alone or in combination with 5-FU demonstrated more extensive inflammation and demyelination at Day 45 than mice treated with PBS. Demyelination was accelerated in infected animals treated with these agents at 45 days but at 70 days a significant difference in extent of demyelination was no longer appreciated between treatment and control groups. Treatment with 5-FU and LE did not convert normally resistant TMEV-infected C57BL/10 mice to demyelination. These experiments support the hypothesis that 5-FU and LE may exacerbate inflammatory demyelination in a susceptible host.

Magnetic resonance imaging in cancer-related lumbosacral plexopathy.

OBJECTIVE: To study the relative utility of computed tomography (CT) and magnetic resonance imaging (MRI) of the lumbosacral plexus in patients with systemic cancer and plexopathy. DESIGN: In a retrospective study, we identified all patients encountered at Mayo Clinic Rochester between 1987 and 1993 with a diagnosis of lumbosacral plexopathy, and we selected for analysis those with MRI scans of the plexus (an abnormal finding was not necessary for inclusion) and a clinical and electrophysiologic appearance consistent with a diagnosis of metastatic lumbosacral plexopathy. MATERIAL AND METHODS: The study group consisted of 31 patients (20 men and 11 women). The types of tumor were as follows: prostatic, 10 patients; colorectal, 7; bladder, 3; cervical, 3; and other, 8. Eighteen patients had received pelvic radiotherapy before diagnosis of lumbosacral plexopathy. All available MRI scans (in 27 patients) were reviewed blinded; the initial imaging report was used if the actual scans were unavailable (in 4). CT had been done in 22 patients, and results for 16 were available for blinded review. Original reports were available for the other six. RESULTS: Direct involvement of the lumbosacral plexus by tumor was evident on 23 MRI studies, and 6 others showed widespread metastatic disease in the region of the plexus. On 13 CT examinations, direct involvement of the lumbosacral plexus by tumor was noted. In four patients, MRI findings were abnormal and CT findings were normal. No patient had abnormal CT findings and normal MRI findings. CONCLUSION: In this retrospective review, MRI was more sensitive than CT for diagnosing cancer-induced lumbosacral plexopathy. Thus, use of MRI should be considered in the diagnostic work-up of patients with clinical and electrophysiologic evidence of plexopathy and suspected systemic cancer.

Pilot study evaluating local anesthetics administered systemically for treatment of pain in patients with advanced cancer.

Based on evidence that suggested that systemically administered local anesthetics might be useful in chronic pain, we initiated a pilot study to evaluate the activity and toxicity of mexiletene and flecainide in the treatment of cancer pain. Twenty-one courses of either mexiletine or flecainide were administered to patients with an Eastern Cooperative Oncology Group performance status of three or better, who were suffering from cancer pain inadequately controlled with opioid analgesics. Pain control was assessed by patient questionnaires to monitor benefit and toxicity. In 17 cases, there was no suggestion of benefit. Two cases had relatively clear-cut analgesic benefit, and two others had some suggestion of mild-to-moderate analgesic relief. Flecainide was relatively well tolerated, but mexiletine appeared to cause nausea and/or vomiting in five of eight patients. This pilot trial suggests that systemically administered local anesthetics can relieve pain in a minority of patients with cancer pain.

Analysis of proliferation markers and p53 expression in gliomas of astrocytic origin: relationships and prognostic value.

Consecutive paraffin sections of 105 astrocytomas and 15 oligoastrocytomas were examined for expression of p53, MIB-1 (Ki-67), and proliferating cell nuclear antigen (PCNA). The tumors had been examined previously for genetic abnormalities and by flow cytometry. Regardless of the tumor's stage and grade and the patient's age and gender, p53 expression was found in 40% of tumors. Although p53 expression was associated with a loss on chromosome 17p and was more frequent in aneuploid tumors, it had no association with survival time. The MIB-1 and PCNA labeling indices increased with increasing tumor grade but showed no association with other clinicopathological parameters. In individual tumors, there was poor concordance between any of the variables (MIB-1, PCNA, and p53). Results for p53 and MIB-1 were similar for both astrocytomas and oligoastrocytomas. The MIB-1 and PCNA values appeared to have prognostic utility in univariate analysis but not after adjusting for patient age and tumor grade. The poor concordance between MIB-1 and PCNA in individual tumors indicates that any one means of assessing proliferative potential in gliomas may not be reliable.

Dysarthria and apraxia of speech associated with FK-506 (tacrolimus).

The immunosuppressive agent FK-506 (tacrolimus) is one of the agents most commonly used to prevent rejection after liver transplantation. Neurologic toxicity related to FK-506 has been reported, including speech disorders; however, a detailed analysis of the speech disorder associated with use of FK-506 has not been presented. Herein we describe a patient who exhibited mutism, then severe apraxia of speech with a concomitant hypokinetic, spastic, and ataxic dysarthria after administration of FK-506. His residual mixed dysarthria, without radiographic evidence of a structural lesion, suggests dysfunction of one or more neurochemical systems. The pathophysiologic mechanisms underlying this intriguing entity remain obscure.

Multifocal inflammatory leukoencephalopathy associated with levamisole therapy.

Cerebral demyelinating disease developed in a patient during adjuvant therapy with levamisole for malignant melanoma. This patient had no evidence of previous neurologic disease. Levamisole was administered for 5 weeks (total dose, 1,500 mg). Over a period of 3 weeks, the patient became progressively confused and ataxic. MRI with gadolinium enhancement demonstrated prominent multifocal enhancing white matter lesions. CSF examination revealed an inflammatory profile. After discontinuation of treatment with levamisole and a short course of corticosteroid therapy, the patient's condition dramatically improved. MRI also indicated improvement. Observations in our patient suggest that the leukoencephalopathy that developed in previously reported patients who received 5-fluorouracil and levamisole may have been caused at least partly by levamisole.

Prognostic factors in gliomas. A multivariate analysis of clinical, pathologic, flow cytometric, cytogenetic, and molecular markers.

BACKGROUND: The ability to divide subsets of patients with glial neoplasms into prognostic groups currently is limited because only a few clinical and pathologic variables are available. The goal of this investigation was to identify biologic factors of potential prognostic value in patients with cerebral gliomas. METHODS: This prospective investigation used clinical, pathologic, flow cytometric, cytogenetic, and molecular genetic variables as potential prognostic factors in 207 patients with newly diagnosed gliomas (153 astrocytic tumors of the fibrillary type, 31 oligodendrogliomas, and 23 pilocytic astrocytomas). Classification and regression tree (CART) analysis was performed as part of the multivariate statistical analysis. RESULTS: The age of the patient and the grade of the tumor were confirmed as strong prognostic factors. Cytogenetic or molecular genetic abnormalities of chromosomes 7 and 10 were associated with poor survival in univariate analysis (P < 0.0001). CART multivariate analysis identified several subsets of patients with different prognoses. In the subset of patients younger than 66.5 years with Grade 4 tumors, the survival time was longer for those with aneuploid tumors than for those with nonaneuploid tumors. In the subset of patients with Grades 1-3 tumors, the survival time was longer for those whose tumors had a %G2M of less than 6.9 than for those whose tumors had a %G2M of 6.9 or greater. CONCLUSION: This investigation provides further evidence that flow cytometry, cytogenetic, and molecular genetic factors that may have prognostic value in patients with gliomas can be identified.

A familial syndrome with cutaneous malignant melanoma and cerebral astrocytoma.

We describe a family in which cutaneous malignant melanoma or cerebral astrocytoma, or both, developed in eight members over three generations. Other malignancies also occurred with a lesser frequency. In two patients with both malignant melanoma and astrocytoma, the brain tumor followed the diagnosis of melanoma by a period of 2 and 10 years and was the primary cause of morbidity and mortality. The findings in this family may represent a newly described genetic disorder.

Herpes zoster-associated meningoencephalitis in patients with systemic cancer.

We reviewed the experience at the Mayo Clinic with neurologic complications related to herpes zoster in patients with systemic cancer. Aside from pain, the most common neurologic complication was zoster-associated meningoencephalitis, which occurred in 9 of 1,125 patients. In these nine patients, the most common underlying malignant lesions were chronic lymphocytic leukemia and lymphoma. All patients in whom meningoencephalitis developed had trigeminal zoster or disseminated zoster. The primary neurologic symptoms were headache, confusion, and somnolence. Nuchal rigidity and fever were uncommon. The response to treatment with acyclovir was generally favorable.