John F. Griffith

Persistent and fatal central-nervous-system echovirus infections in patients with agammaglobulinemia.

We observed persistent ECHOvirus infection of the central nervous system, as defined by continued presence of isolatable virus in cerebrospinal fluid, in five patients with agammaglobulinemia. The immunologic deficit in each was characterized by absence of surface-immunoglobulin-bearing B lymphocytes and of lymph-node cortical follicles, but normal T-cell function. ECHOviruses 30, 19, 9 and 33 were recovered from cerebrospinal fluid for periods varying from two months to three years. The patients had few signs of acute central-nervous-system infection. Three of the five patients had a dermatomyositis-like syndrome, with peripheral lymphocytes that reacted with anti-human leukemia-specific primate and rabbit serums in a cytotoxicity assay. These data suggest that intact B-cell function is essential for eradication of ECHOvirus infection of the central nervous system.

Transient Blindness Following Head Injury in Children

Abstract Seven patients aged six to 16 years, had transient total blindness following seemingly trivial blunt head trauma. The blindness persisted for a few minutes to three to four hours. With one exception, there were no other ocular abnormalities. Bilateral occipital slowing was noted on the electroencephalogram in the early post-traumatic period. Restlessness and agitation were prominent during the period of blindness, but behavior reverted to normal with the return of vision. Recovery was complete in every case. The type of trauma frequently involving the parieto-occipital regions, the prominence of posterior slowing on the electroencephalogram and the absence of associated ocular abnormalities when the blindness was complete suggest some type of temporary cerebral dysfunction, although the precise mechanism is obscure.

Subacute sclerosing panencephalitis, laboratory findings in 6 cases.

SINCE THE REPORT by Connolly et al.1 earlier this year documenting unusually high serum and cerebrospinal fluid (CSF) levels of measles antibodies in three patients with Subacute Sclerosing Panencephalitis ( SSPE) , others293 have reported similar elevations of antibody titers in the sera of patients with this disease. Hemagglutination-inhibition (HAI) and complement-fixing (CF) antibodies were usually determined, but in the two cases of Freeman et a].,* measles virus-neutralization (VN) and fluorescent antibody (FA) titers were studied also. When these immunologic data are considered, along with the observation in brain biopsy material of immunofluorescent staining specific for measles by both the direct and indirect methods and the electronmicroscopic photographs43 of particles resembling a myxovirus in size and configuration, the conclusion that measles virus is intimately involved in the pathogenesis of this disease is inescapable. This report is submitted to corroborate and extend the findings of antibody rises in this condition and to outline an attempt, albeit negative to date, to isolate virus from the brain of one autopsy specimen. Sera and CSF from six well-studied cases of SSPE were tested for measles VN antibodies (employing an inoculum of approximately 100 TCID,, of virus with serum dilution in AH-1 [GMK] cell cultures, a continuous line of grivet monkey kidney). Aliquots of serum from 4 of these patients and CSF from 2 of them were sent to Dr. Adels at the National Institute of Neurological Disease and Blindness for HAI, CF and FA titer determinations. These latter results which are included in the report presented at this same meeting by Dr. Adels and his associates confirm, by these additional methods, the elevations we found in VN antibody titers. In each case the clinical features included a progressive dementia with rhythmic myoclonic jerks and progressive motor disability leading ultimately to immobility and severely altered awareness. Additionally, the classical electroencephalographic changes of regular synchronous spike-wave complexes interspersed with relative electrical silence and the characteristically elevated CSF gamma globulins were present. Biopsy or autopsy specimens, available from 5 to 6 patients, showed the neuropathological lesions typical of SSPE although inclusions were detected in only 3 of the 5. The essential clinical and laboratory findings in each case are summarized in table. Patient C.S., from whom fresh autopsy material was recently made available for virus studies, had died within 4 months of the onset of her illness. I t had begun with subtle changes in personality progressing to include abnormalities of speech and motility. She developed severe bilateral spastic rigidity with marked dystonic posturing of her right side. Rhythmic myoclonic jerks, both light and sound sensitive, were so violent in the terminal stage of her illness that she had to be restrained to prevent her falling from bed. Throughout her illness she remained conscious and ostensibly alert. No impairment of cranial nerve function was observed. She died quite unexpectedly, presumably the result of a synergistic effect of sedative-anticonvulsant medication. Representative brain sections obtained within 4 hours of her death were handled in the following manner. After an initial wash in Hanks’ balanced

1100 THE ARRHENIUS PLOT OF HEPATIC MICROSOMAL GLUCOSE-6-PHOSPHATASE ACTIVITY OF THE CONGENITALLY JAUNDICED (GUNN) RAT

The failure of the Gunn rat to conjugate bilirubin results from either defective (or absent) bilirubin UDP-glucuronyl transferase or from a defect in the membrane environment of that enzyme. The latter possibility was investigated by constructing Arrhenius plots from 38-8°C of microsomal glucose-6-phosphatase activity of Gunn (jj,n=6), Wistar (JJ,n=9) and heterozygote (Jj,n=8) rats. This enzyme was studied because the Gunn rat is not defective in glucose-6-phosphatase, and this enzyme is tightly bound to the microsome. The plots of jj, Jj and JJ were identical in the following ways: a) the specific activity at 37°C was 2.51 μmol hydrolyzed/mg protein/10 min indicating no jj defect in enzyme activity; b) there was a change in slope at 35°C probably indicating a change in protein structure; c) the energy of activation was 12800 cal/mol. However, a clear difference was observed in the following way: JJ demonstrated a discontinuous plot indicating a lipid phase change at 11°C, but the plot of jj was a continuous straight line to 8°C. Jj exhibited an intermediate discontinuity at 8°C. This shift in the phase change to colder temperatures indicates a difference in membrane fluidity among groups. The proposed explanation for the deficient activity of bilirubin UDP-glucuronyl transferase in the Gunn rat is a difference in membrane fluidity which results in an anomalous environment for the enzyme.

Histiocytosis X with Benign Intracranial Hypertension

A three‐year‐old child is reported who presented with raised intracranial pressure, skin rash and chronically discharging ears. Pneumoencephalography revealed a normal ventricular system, and subsequent histological study of the skin and temporal bone showed the classical changes of histiocytosis X.

Slow Virus Infections

Subacute sclerosing panencephalitis, together with some other neurologic disorders, fits the definition of a “slow infection” in requiring an incubation period of years (rather than days or weeks), and its viral origin now appears to be confirmed by the recovery of an agent resembling measles virus from cultures of affected brain material. The probable natural history of the disease is delineated.

NERVOUS SYSTEM MANIFESTATIONS OF CYTOMEGALOVIRUS (CMV) INFECTION

CONGENITAL cytomegalovirus (CMV) infection classically presents in the newborn period with hepatosplenomegaly, petechiae, chorioretinitis, jaundice and lethargy. Clinically, it is difficult or impossible to differentiate this condition from other congenital and neonatal infections, especially toxoplasmosis, syphilis, rubella and generalized herpes simplex. Periventricular calcifications are often seen on skull roentgenograms and ‘owls eye’ inclusion bodies may be detected in cells of the urinary sediment. The diagnosis can now be positively established by the isolation of virus in tissue culture inoculated with specimens of blood or urine. In addition, an elevated level of immunoglobulin M (IgM), specific for

1139 PARATHYROID (PTH) AND ANTIDIURETIC HORMONE (ADH) IN REYE-JOHNSON SYNDROME (RJS)

From the metabolic standpoint, several features of RJS implicate a role for cAMP in the pathophysiology of this disease. ↑ plasma cAMP is found in RJS to corroborate this possibility. In the presence of a normal degrading system, cAMP should not be expected to be ↑ in the urine. However, 25% of cases have ↑ cAMP excretion. Since PTH and ADH are both known to ↑ cAMP production by the cells of the renal tubules, these hormones were measured in plasma, retrospectively, in untreated RJS patients. ↑ ADH and PTH levels were found which correlated with the severity of the disease. In two patients, a rapid decline in the PTH levels was seen in 3-5 hours. No significant changes in serum Ca, Mg, PO4, and osmolality were noted. These findings add two more hormones in addition to insulin, glucagon, ACTH, cortisol, GH, prolactin, and the catecholamines which are increased in the complexity of findings in RJS. A model which could accommodate some of these findings and lend insight to a possible mechanism involving Ca translocation whereby an underlying membrane lesion might be further aggravated by these abnormalities is proposed.This work was supported in part by a grant from the USPHS, NIH HD 11657.

EXPERIMENTAL HSV ENCEPHALITIS: EFFECTS OF TREATMENT WITH CYTOSINE ARABINOSIDE

The effects of cytosine arabinoside (cytarabine) on survival and brain virus concentration were studied in groups of young mice with experimental herpes simplex virus (HSV) encephalitis. Toxic dosages of drug were purposely employed in order to ensure maximum anti-viral activity in the brain. Encephalitis was established by direct intracerebral innoculation of previously titered virus, known to be sensitive to this drug in vitro. Treatment was begun at intervals prior to and following introduction of virus. The concentration of virus per gram of brain was determined at intervals during the 4 day treatment course and on completion of drug administration.During the initial 3 days of infection, the brain virus concentration in treated animals was significantly lower than in the infected, untreated control group. This was also noted when a more concentrated drug dosage was used. There were no survivors in either group although the clinical courses differed. The brains of infected animals showed a necrotizing encephalitis with polymorphonuclear and mono-nuclear cells, focal hemorrhage and rare inclusion bodies.Large doses of cytosine arabinoside administered in this way have a significant but transient effect on brain virus concentration but do not alter the clinical course of disease. This is the first in vivo demonstration of the activity of this agent against HSV replication in the CNS.

NORMAL ELECTROENCEPHALOGRAMS IN SUBACUTE SCLEROSING PANENCEPHALITIS (SSPE)

Eleven cases of SSPE from the rural southeast were studied at Duke from 1968-73. Eight patients had a history of measles immunization and 5 of these reportedly had antecedent natural measles. The diagnosis was confirmed in every case either by the ultrastructural demonstration of virus nucleocapsids in brain tissue or the detection of anti-measles antibodies in the CSF.Six of the patients had normal EEGs when first examined, an average of 6 months after the onset of illness. This group did not differ from those with abnormal EEGs in any important detail including age, sex, measles antibody titer, severity or duration of illness or the length of survival. All of the EEGs eventually became abnormal, 4 with the classical suppression burst pattern considered diagnostic for SSPE. At the time of the normal tracing, one patient had well developed myoclonus.These findings indicate that a normal EEG is common in SSPE even when the clinical disease is moderately advanced. This re-emphasizes the diagnostic importance cf CSF measles antibodies when other studies are normal.