West Nile encephalitis: the neuropathology of four fatalities.

West Nile virus was identified by immunohistochemistry (IHC) and polymerase chain reaction (PCR) as the etiologic agent in four encephalitis fatalities in New York City in the late summer of 1999. Fever and profound muscle weakness were the predominant symptoms. Autopsy disclosed encephalitis in two instances and meningoencephalitis in the remaining two. The inflammation was mostly mononuclear and formed microglial nodules and perivascular clusters in the white and gray matter. The brain stem, particularly the medulla, was involved most extensively. In two brains, cranial nerve roots had endoneural mononuclear inflammtion. In addition, one person had acute pancreatitis. On the basis of our experience, we offer recommendations for the autopsy evaluation of suspected WNV fatalities.

The pathology of human West Nile Virus infection.

West Nile Virus (WNV) was identified by immunohistochemistry (IHC) and polymerase chain reaction (PCR) as the etiologic agent in 4 encephalitis fatalities in New York City in the late summer of 1999. The fatalities occurred in persons with a mean age of 81.5 years, each of whom had underlying medical problems. Cardinal clinical manifestations included fever and profound muscle weakness. Autopsy disclosed encephalitis in 2 instances and meningoencephalitis in the remaining 2. The inflammation was mostly mononuclear and formed microglial nodules and perivascular clusters in the white and gray matter. The brainstem, particularly the medulla, was involved most extensively. In 2 brains, cranial nerve roots had endoneural mononuclear inflammation. In addition, 1 person had acute pancreatitis. Based on our experience, we offer recommendations for the autopsy evaluation of suspected WNV fatalities.

Neurofibromatosis and other disorders among children with CNS tumors and their families.

We conducted a population-based case-control study with 338 patients, less than 15 years of age, diagnosed with a primary tumor of the central nervous system from January 1968 through December 1977 in 53 New York State counties. The study also included 676 controls selected from the birth certificate files of the New York State Department of Health. We collected information on neurofibromatosis and congenital anomalies in study subjects, their siblings and parents by telephone interview with the mother of each case and control. We obtained supplemental information on neurofibromatosis in the patients and their families from hospital medical records. This study confirmed the strong association of neurofibromatosis with risk of CNS tumors. Thirteen cases and no controls had neurofibromatosis. Two fathers and 3 mothers of cases had neurofibromatosis. Five cases had siblings with neurofibromatosis. None of the first-degree relatives of controls had neurofibromatosis. We observed a relative risk of 4.49 for history of seizures. Seizures are often among the presenting symptoms for CNS tumors. We observed no difference between cases and controls in the occurrence of congenital anomalies. There was a nonsignificant excess of congenital anomalies among siblings of cases compared with controls. This decreased to 1.13 when adjusted for number of siblings.

An epidemiologic case-control study of central nervous system tumors in children and parental occupational exposures.

A population-based case-control study was conducted with 338 patients less than 15 years of age who were diagnosed with a primary tumor of the central nervous system from January 1968 through December 1977 in 53 contiguous New York counties. The study also included 676 controls who were selected from the birth certificate files of the New York State Department of Health. Parental occupational exposures at the time of each child's birth and at the time of tumor diagnosis were derived from maternal interviews. The current data set failed to show any consistent association between childhood central nervous system tumor risk and paternal occupational exposures to hydrocarbons or to electromagnetic fields, or employment in the aerospace industry or pulp and paper manufacturing. Findings for occupational exposures to ionizing radiation were also inconsistent. A positive association was observed between central nervous system tumor risk and paternal exposures to ionizing radiation based on industrial codes. Odds ratios ranged from 1.71 to 2.15. This association was not observed when paternal occupational titles were used to define exposure (range of odds ratios, 1.01-1.10). Maternal exposures to ionizing radiation were not related to risk regardless of the classification scheme used.

A clinicopathological study of 323 patients with oligodendrogliomas.

All patients with oligodendrogliomas (554) from the repository of the Armed Forces Institute of Pathology were retrospectively analyzed. The pathological diagnosis was confirmed in 323 patients and each case was graded according to a previously established grading system. The clinical features of these 323 verified cases of oligodendroglioma are presented, analyzed, and compared with findings in previous studies. There is a significant age skew according to tumor grade, with 68% of patients with grade A tumors under 40 years and 83% of patients with grade D tumors over 40 years of age. Headache was the most common symptom, followed by seizure, visual loss, papilledema, paralysis, and dementia. No symptoms showed a statistically significant correlation with tumor grade. However, tumor grading allowed significant prognostic statements to be made. Attention is drawn to several often neglected symptoms of oligodendrogliomas: ataxia, hemorrhage, stroke, and cerebrospinal fluid spread. This is, to our knowledge, the largest clinicopathological study of oligodendrogliomas to date.

Myoadenylate deaminase deficiency and malignant hyperthermia susceptibility: is there a relationship?

Muscle biopsies from 35 patients referred for possible malignant hyperthermia were subjected to contracture testing with halothane, caffeine, and the combined agents, histopathological and fiber-type-distribution analysis, and quantitative assay of three major muscle enzymes: adenylate deaminase, adenylate kinase, and creatine kinase. Adenylate kinase and creatine kinase were in the normal range in all biopsies and each averaged 92% of expected normal value when corrected for their fiber-type distribution. Of the 14 cases with a positive halothane test, 2 had primary myoadenylate deaminase deficiency, and 5 others had low levels of this enzyme (less than one-third normal). In contrast, only 3 of 21 cases negative to halothane testing had low adenylate deaminase levels, and none were deficient. This association was significant by several statistical tests, although it would not be highly predictive for an individual case. A positive halothane test also correlated with a high type 2 fiber contribution, but this was probably secondary, since cases with low enzyme levels had significantly higher type 2 fiber areas. Caffeine contractures did not correlate with either low enzyme levels or with fiber-type distribution. Sixty percent of the biopsies were entirely normal histologically, and showed a significant correlation with a negative combined contracture test. Data on the one family included in this study suggest separate inheritance of the trait for myoadenylate deaminase deficiency and the trait for positive contracture tests. The present findings suggest that patients with myoadenylate deaminase deficiency (and the carrier state as well) may be at increased risk of malignant hyperthermia when subjected to anesthesia.

Spinal metastases. A rare mode of presentation of brain tumors.

An analysis of more than 18,000 primary central nervous system (CNS) tumors revealed only 18 cases (0.01%) in which dropped spinal metastases had caused the presenting symptoms. This group included 11 males and 7 females in whom there was no history of surgical intervention or irradiation. Primitive neuroectodermal tumors ( PNET , medulloblastoma), comprised the largest group (11 patients) followed by high-grade astrocytomas (anaplastic and glioblastoma) (5 patients). One case each of germinoma and ependymoma were also identified. The clinicopathologic data of these cases, and a brief review of the literature are presented.

Interstitial 5'-nucleotidase stain for frozen biopsy specimens of skeletal muscle. A useful adjunct in the diagnosis of polymyositis.

We applied a simple lead salt-based stain for interstitial and vascular 5'-nucleotidase to 150 muscle biopsy specimens. No reaction was obtained with 2'- or 3'-adenosine monophosphate, indicating that the stain was specific, and distinct from phosphatases. Staining was not inhibited by alpha, beta-methylene adenosine 5'-diphosphate, but was prevented by formaldehyde fixation or by brief immersion in octoxynol 9 (Triton X-100). Nucleotidase stains the following specific histologic sites that distinguish it from alkaline phosphatase: the intima and adventitia of medium-sized and large arteries, perineural and muscle spindle sheaths, and tendon insertions. Aside from these structures, normal muscle shows little reaction, as the sarcoplasm and sarcolemma do not stain. Neither of these enzymes shows a compensatory increase, histochemically, in myo-adenylate deaminase deficiency. In Duchenne's muscular dystrophy, however, and particularly in inflammatory myopathy, interstitial staining of 5'-nucleotidase is increased, leading to investment of most muscle fibers in the affected area. The stain rarely identifies regenerating fibers. Although alkaline phosphatase commonly shows a corresponding increase in interstitial staining, we encountered six cases of inflammatory myopathy in which this was absent, despite pronounced endomysial staining in the 5'-nucleotidase reaction. 5'-Nucleotidase thus appears to provide a valuable adjunct in the diagnosis of inflammatory myopathy.

Levels of adenylate deaminase, adenylate kinase, and creatine kinase in frozen human muscle biopsy specimens relative to type 1/type 2 fiber distribution: evidence for a carrier state of myoadenylate deaminase deficiency.

Myoadenylate deaminase deficiency is believed to reflect a genetic deficiency of skeletal muscle, but its pattern of inheritance has not been established. We examined, histochemically and by quantitative biochemical assay, muscle biopsy specimens from 3 putative carriers of this disorder. Adenylate kinase and creatine kinase were assayed in parallel with adenylate deaminase in order to establish enzyme activity ratios and the variation of each enzyme with fiber-type distribution. Control tissue consisted of 34 biopsy specimens without notable abnormalities from 30 patients, and included 4 specimen pairs with disparate fiber-type contributions. By linear regression analysis, adenylate deaminase level averaged 2.8-fold higher, and adenylate kinase 4.5-fold higher, in type 2 than in type 1 fibers, whereas creatine kinase level did not differ. The slopes of the regression lines resulting from analysis of the four specimen pairs from individual patients agreed well with the overall regression line in each plot. The 3 putative carriers had adenylate deaminase levels 2.5 to 5.7 times lower than the mean control value for their fiber-type distribution, but at least 20 times higher than their enzyme-deficient kinfolk. This finding indicates that a carrier state does exist, and that the deficiency state reflects an autosomal recessive inheritance pattern. Three additional biopsy specimens were excluded from evaluation when preliminary analysis showed elevated adenylate kinase/adenylate deaminase ratios that were outliers at the 1% level. This result suggests a carrier incidence of 10% in the muscle biopsy specimen population, which would markedly bias population estimates if undetected.

Grading of oligodendrogliomas.

The purpose of this study was to determine the effectiveness of histologic grading of oligodendrogliomas in a retrospective study. 323 cases with adequate clinical information and confirmatory histological material were acquired from the files of the AFIP. A grading system was devised using the following criteria: endothelial proliferation, necrosis, nuclear/cytoplasmic ratio, cell density and pleomorphism. The grading system separated 23% of the cases into grade A, 49% into grade B, 22% into grade C and 6% into grade D. Statistical analysis showed that the grading system significantly correlated with survival (P less than or equal to 0.01). Median survival periods for each grade were as follows: grade A, 94 months; grade B, 51 months; grade C, 45 months; grade D, 17 months. Of the five factors comprising grade, only pleomorphism was significantly correlated with survival by itself (P less than or equal to 0.01). It is concluded that grading of this form of glioma can be an effective estimate of prognosis.

The course of alcoholic-nutritional peripheral neuropathy.

63 patients with alcoholic-nutritional peripheral neuropathy were given neurologic, electrophysiologic and nutritional examinations. 24 of these patients were reexamined later in the course of their disease, after from 2 to 72 months (mean 33). Alcoholic-nutritional neuropathy appeared and worsened after bouts of heavy alcohol intake and malnutrition. Initially it was sensory and symmetric in character, with prominent involvement of the posterior tibial nerves. With repeated attacks it became more proximal, more motor, and associated with more severe slowing of nerve conduction velocity. 11 of the patients were able to stop drinking alcohol. Initial subjective improvement was seen within the first week or two, but substantial improvement was not seen for 5 to 6 months. Most leg motor nerve velocity improved at a mean rate of increase of 0.12 M/sec per abstinent month. Large motor units and slowed nerve conduction persisted in "cured" patients. The largest motor units detected in the legs grew, despite alcohol intake.

Diffuse meningeal rhabdomyosarcoma.

Pure rhabdomyosarcomas are extremely rare as primary tumors in the cranial vault. In this instance, a 25-year-old man had symptoms and signs of chronically increased intracranial pressure. A biopsy of the meninges of his posterior fossa was performed revealing a spindle-cell sarcoma. Ultrastructural evidence of striated muscle differentiation and cross striations was present. The patient died of pulmonary emboli. Complete autopsy failed to disclose tumor anywhere except the leptomeninges. The presence of this tumor indicates that a rhabdomyosarcoma can arise from the meninges without a preexisting glioma or teratoma.

Stain for skeletal muscle adenylate deaminase. An effective tetrazolium stain for frozen biopsy specimens.

Procedures for staining frozen sections of human muscle biopsy specimens for adenylate deaminase are outlined. The preeminent role of this procedure is as a survey stain for myoadenylate deaminase deficiency, a new and common muscle enzyme deficiency, an example of which is illustrated. Discrimination of type I and II muscle fibers with this stain is based on color differences rather than density differences. Color photomicrographs illustrate the variations in staining that may be encountered, and experimental controls to verify the validity of the stain are summarized.

The carcinomatous neuromyopathy of oat cell lung cancer.

A prospective controlled clinical-neurophysiological-pathological study of 71 patients with oat cell carcinoma of the lung revealed no increased incidence of peripheral neuropathy at the initial stages of illness. All patients developed neuropathy by the time they had lost 15% of their body weight, but the neuropathy was less severe than in 20 age-matched alcoholic patients with an equal degree of weight loss. The weight loss and peripheral neuropathy progressed with atrophy of type II (adenosine triphosphatase-positive) muscle fibers out of proportion to the patient's loss of body weight. By 40% body weight loss, all the patients had moderate symmetrical peripheral neuropathy, 6 had proximal brachial or lumbosacral plexus metastases, and 9 had distal pressure palsies. Mononeuritis multiplex developed in only 1 patient, who had diabetes mellitus. Two patients developed Eaton-Lambert syndrome, which resolved in 1 when chemotherapy controlled the systemic tumor, with no protein in the tumor postmortem which could produce the characteristic electromyographic findings of the syndrome.

Pathology of dementia.

A group of diseases of the brain characterized by dementia have been discussed. The pathologic features of each were described and illustrated. It seems that, in summary, several points merit emphasis. First of all, as more people survive to the seventh, eighth, and ninth decades, the most common dementia, senile Alzheimer's disease, will become a more significant public health problem. Second, while at the present time there is no successful therapy available, there are some glimmerings of hope on the horizon. The discovery of the agent of Creutzfeldt-Jakob disease seems to have placed us on the fringe of a whole new series of advances. A novel type of disease agent awaits characterization and definition, and there are hints that similar agents could be responsible for the development of the degenerative diseases, perhaps in conjunction with environmental toxins and in the medium of a permissive genetic background. In the case of Huntington's chorea, it seems reasonable that a pharmacologic agent could be found to control the symptoms such as L-dopa therapy has done for patients with Parkinson's disease. It may develop, however, that such an agent will control the choreiform movements but will not influence the dementing condition.