The acute event is over. The patient is "cured" and returns home. But unlike many infections that, once successfully eradicated iwith antibiotics or spontaneously resolved are ino longer a problem, infections of the nervous system often produce continuing and sometimes progressive symptoms that interfere with the optimal adaptation of the person afifected. The complexity of the nervous system, limitations of its capacity to respond to infections, and the possible global effects of small all contribute to the potentially devastating results of infections of the nervous system. This review examines some of the pathophysiologic mechanisms that produce long-term complications of nervous- system infections, the clinical manifestations of these events and their identification, and methods of management.
Recent awareness of more subtle diffuse effects of nervous- system infections, such as bacterial meningitis, has stimulated a more careful approach to predictions about adaptation of children who recover, apparently completely, from nervous- system infections. For example, in a follow-up study of 80 children with bacterial meningitis1 who were discharged without obvious neurologic sequelae, 34 per cent had one or more permanent neurologic defects consisting of nerve deafness, visual and speech defects, convulsive episodes, poor coordination, and facial paresis. In a follow-up study oiHemophilus influenzae meningitis2 (the most common bacterial pathogen in childhood meningitis) in 86 patients, 29 per cent of the survivors had severe or significant handicaps and 14 per cent had possible residua. In a similar review3 of 33 survivors of H. influenzae meningitis, 27.5 per cent had definite residual handicaps. These studies were all done in populations receiving excellent antibiotic management.
Thus, approximately one-third of children who have been "cured" of bacterial meningitis have residual handicaps that could interfere with their ultimate optimal productiveness or adaptation. This figure becomes much more important when the incidence of bacterial meningitis among children is examined. Between 21,000 and 30,000 cases of bacterial meningitis per year in the United States4 would produce significant neurologic residua in 7,000 to 10,000 children per year. Furthermore, many of the children described in the studies referred to have multiple handicaps, complicating both their management and prognosis.5
Bacterial meningitis, although a frequent cause of chronic neurologic sequelae, is only one of a number of infectious disorders that can permanently affect the nervous system. Viruses both in fetal life and after birth, protozoa, and rickettsia and fungi can all produce long-term effects following nervous- system infection. Although the pathogenetic mechanisms differ somewhat and therefore the clinical spectrum of symptoms is variable, many of the same sequelae are produced by each of the different organisms and different stages of development. For this reason, the infectious disorders that produce permanent neurologic complications will be discussed by the type of organism and stage of development at the time of infection, with their specific "syndromes" or recognizable symptom complexes as well as individual symptoms. For each infectious process, a brief description of pathogenesis will precede the presentation of the clinical manifestations.
INFECTIONS IN UTERO
Many organisms are known to produce damage to the nervous system during fetal development, including viruses (rubella, cytomegalovirus, herpes simplex), bacteria (syphilis), and protozoa (toxoplasmosis). Of these, rubella has been the most thoroughly studied, both clinically and pathologically. In their classic description of congenital rubella encephalitis, Desmond et aL6 clearly demonstrate that the nervous- system infection of congenital rubella, although beginning in utero, is an ongoing event with symptoms of nervous-system infection and virus shedding in the spinal fluid as late as 18 months after birth. This information is helpful in evaluating the results of follow-up studies, some of which tend to minimize the nervous- system effects of congenital rubella in later life.7 The pathologic studies of the infants who died with congenital rubella revealed8 chronic leptomeningitis, areas of liquefactive necrosis, and glial cell proliferation in basal ganglia, white matter, midbrain, and spinal cord, as well as microscopic vasculitis. Two infants who had no overt neurologic signs had either leptomeningitis or areas of focal necrosis in white matter.
The clinical results of such pathologic changes are discussed by Dr. Ziring in his article elsewhere in this issue. An excellent outline has also been published by Dr. Cooper and his associates.8 In the latter report, out of a study population of 376 children with congenital rubella, 170 had psychomotor retardation ranging from mild intellectual impairment (40) to severe retardation (46) with spastic quadriparesis. This, combined with a high incidence of deafness (252 of 376} and visual loss due to cataracts and glaucoma, leads to a devastating disability in many of these children, especially in view of the demonstrated need for higher intellectual functioning in deaf children in order for them to obtain significant educational achievement.5
Although rubella is the best -documented congenital viral infection affecting the nervous system, cytomegalovirus (CMV) is now considered by many to be a major contributor to long-term disability. The profound effects of infection in utero have been documented - including microcephaly, preventricular calcifications, spastic diplegia, seizures, deafness, and chorioretinitis.9 However, this "syndrome" probably represents only a minority - i.e., the more seriously infected infants identified at birth. A recent prospective study10 of 8,644 newborns found 53 with IgM antibody against CMV in their cord blood. They had a slight but significant diminution in IQ compared with their age-matched controls. More important, bilateral profound hearing loss was present in three of 40 children with positive cord blood anti-CMV IgM, an abnormality that ordinarily occurs in one in 1,000 of the general population. This study is important because these children were all considered normal at birth, indicating that at least some childhood learning problems and "idiopathic" deafness may be attributable to silent in utero nervous- system infections.
Other infecting agents, such as varicella herpesvirus and toxoplasmosis (a protozoon), are known to cause human fetal infections of the central nervous system. In utero herpesvirus infection is frequently overwhelming and fatal, and the outcome of survivors has been poorly documented. Toxoplasmosis produces a generalized disorder with predominantly neurologic involvement,11 with mental retardation, convulsions, spasticity, deafness, and micro- or hydrocephalus. No prospective studies of the type described for CMV have been performed for either herpesvirus or toxoplasmosis, and therefore the results of less severe in utero infections are not known. One might speculate as to the possible results of less severe involvement of the nervous system in these diseases as well.
One congenital infection, syphilis, which can produce neurologic and mental sequelae, must be mentioned here in view of the rising incidence of venereal disease. Hallgren and Hallström,12 in follow-up study of 328 cases of congenital syphilis, demonstrated a higher incidence of mental subnormality and behavior disorders associated with definite neurologic abnormalities than in the general population. This preventable congenital spirochetal infection may contribute to the incidence of mental retardation unless measures are taken to reduce the incidence of syphilis in the general population.
In summary, a variety of organisms - viral, bacterial, and protozoan - produce CNS infections in fetal life that have long-term consequences, ranging from mild depression of cognitive function to profound mental retardation, motor deficits, chronic seizure disorders, deafness, blindness, and combinations of mental motor deficits and special sensory handicaps. These occasionally cluster into "syndromes," as in congenital rubella and classic cytomegalovirus infections, but in all probability more often result in less severe consequences, such as mild learning disabilities or partial deafness.
POSTNATAL VIRAL INFECTIONS
Herpesvirus hominis is considered the most common sporadic or nonseasonal cause of virus encephalitis in this country.13 This sporadic form is commonly due to the type I strain. CNS infection with herpesvirus hominis encephalitis is usually in the form of a severe necrotizing or hemorrhagic encephalitis, with fever, headache, mental confusion, and psychologic disturbances present early in the disease. Signs of focal cerebral dysfunction, focal seizures, dysphasia, and hemiparesis then develop. Although the mortality in documented cases is high, this may be a spurious phenomenon - owing to the difficulty in identifying the disorder in life, requiring brain biopsy for diagnosis. The use of brain biopsy is reserved for the more severe or progressive cases, which are often fatal, and will bias the diagnosis towards the more severely involved. Thus, reports of sequelae will be equally biased toward more severe cases, leaving us with little or no information about the true incidence of permanent residual impairments in this disorder.
A more adequate view of the long-term sequelae of CNS viral infections can be obtained by examining the work of Sells et al.,14 who did a controlled follow-up study of 19 children with documented enterovirus infections. Children whose illness occurred during the first year of life were found to have significantly smaller mean head circumferences, significantly lower mean IQ scores, and depressed language and speech skills compared with a matched comparison group. No differences could be found for children over one year of age. This susceptibility to neurologic damage from viral infections in the immature nervous system is corroborated by Palmer and Finley,15 who studied the late sequelae of 500 children with Western equine and St. Louis encephalitis following a California epidemic from 1945 to 1954. In the group whose infection occurred under three months of age, 44 per cent had residual effects of their infection, including continuation of convulsions, pronounced pyramidal and extrapyramidal signs, along with mental retardation. The incidence of clear-cut residua in children between three months and one year at the onset of their disorder was 25 per cent; in those over one year of age the residua were milder, with convulsions more easily controlled and less severe mental and motor involvement. In this study no "controls" were used to assess the possibly milder effects, in terms of learning abilities or psychologic disturbances, that might be attributable to these viral infections in children who had no gross neurologic residua.
Rosenberger16 has speculated that the apparent increase in residua in children affected at a younger age is doe to an effect on brain growth, which he attributed either to a "lag" in myelination, occurring very rapidly in the first year of life or, more likely, to abnormalities in dendritic branching, which also proceeds rapidly during this critical period in brain growth.17 Whatever the underlying pathogenetic mechanism, the importance of these studies is to emphasize the effect of age on the incidence and severity of neurologic sequelae in childhood viral infections of the nervous system and to point out again that children who have apparently recovered completely from their infections may have subtle neurologic residua that will influence their ultimate ability to adapt in our highly competitive culture.
Another postnatally acquired viral infection, poliomyelitis, was once a significant cause of chronic motor disability secondary to lower motor neuron involvement. The incidence of this disorder in the pediatrie age range at present no longer warrants a detailed presentation. This is a tribute to the progress of immunization, the most important tool we have for the prevention of the disabilities outlined in this review.
PROGRESSIVE VIRUS DISORDERS
Recently two progressive disorders, subacute sclerosing p anen cephalitis (SSPE)18 and a progressive encephalitis following rubella (congenital or acquired), have been related to virus infection, the former with measles (rubeola)19 virus and the latter with rubella.20 These disorders are similar in that there is a long latency between the acute viral infection and the insidious development of progressive neurologic symptoms, with the gradual onset of behavioral changes, dementia, ataxia, spasticity, myoclonus, and eventual death. In both disorders, elevations of serum IgGspecific antibodies have been identified and production of specific IgG in the nervous system has been demonstrated, as well as viral antigen within the nervous system. They differ primarily in clinical presentation, electroencephalographic findings, and pathology.20
Progressive rubella pan encephalitis (PRPE) is characterized by significant ataxia, present at the onset, and spasticity, which does not develop until later. The prominent recurrent myocionic seizures seen in the late stages of SSPE (rubeola) are uncommon in PRPE.20 The prominence of ataxia in the clinical presentation of PRPE is a reflection of significant cerebellar atrophy, seen both on pneumoencephalography and on pathologic examination. The electroencephalogram in SSPE generally has a characteristic pattern of periodic bursts of high-voltage slowing followed by low- voltage or flat activity (the socalled suppression- burst pattern), whereas in PRPE the changes are less specific and consist mainly of diffuse irregular slowing. Although PRPE and SSPE are similar pathologically in that they both show evidence of diffuse encephalitis in both gray and white matter with perivascular round-cell infiltrates and demyelination, they differ significantly in the presence of amorphous PAS-positive deposits in the walls of blood vessels in cerebral white matter, present prominently in PRPE but not in SSPE.20
Thus, in the spectrum of late complications of viral infection, progressive degenerative disease must be considered a significant clinical entity, and latent infection with rubella or rubeola virus must be considered in the differential diagnosis in children with progressive neurologic disorders. Since PRPE can follow either congenital rubella or rubella acquired later in childhood, this disorder must be considered in children known to have congenital rubella as well as in children who have no stigma of congenital infection.
Rocky Mountain spotted fever, the most commonly recognized rickettsial disease in the United States, causes a diffuse vasculitis involving many organ systems, including the central nervous system.21 During the acute phase, headache, mental confusion, and muscular tremors are noted and are often accompanied by focal neurologic signs, such as extensor plantar responses and clonus. In patients who die in the acute phase, scattered arteriolar infarcts and small granulomas are noted in the brain.
In a follow-up study of 37 patients of all ages who recovered from Rocky Mountain spotted fever, Rosenblum et al.21 found 21 patients with some residual neurologic sequelae ranging from emotional lability and memory loss to recurrent convulsions and mental retardation. Six had definite abnormal neurologic findings on examination, and 12 had definitely abnormal electroencephalograms. The severity of the residua was variable and did not correlate well with the appearance of neurologic symptoms during the acute phase, emphasizing the need for careful neurologic follow-up in patients recovering from rickettsial infections.
POSTNATAL BACTERIAL INFECTIONS
The pathology of bacterial meningitis in the newborn period and in later childhood has been extensively reviewed.22,23 The importance of these studies is to emphasize that the inflammatory response is not limited to the meninges in this disorder but, rather, is a vasculitis, with extension of the inflammatory process to the walls of blood vessels causing both venous and arterial occlusions. These vascular reactions produce focal and diffuse cortical infarcts, leading to extensive neuronal loss. The additional role of "toxins" and anoxia is still not fully elucidated.
Destruction of ependyma and subsequent glial scarring can produce obstruction of the aqueduct of Sylvius and/or foramina of Luschka, causing noncommunicating hydrocephalus, while chronic meningea! fibrosis and arachnoiditis can produce obliteration of the subarachnoid space, causing communicating hydrocephalus.22
The heavy involvement of the basal meninges and the contiguous involvement of the cranial nerve roots probably explain the significant cranial nerve dysfunction during the following bacterial meningitis (although direct involvement of the cochlea and vestibule has been described).24 The most important functional loss is due to involvement of the eighth nerve, leading to unilateral or bilateral nerve deafness and vestibular involvement.
The clinical manifestations of these pathologic changes in the survivors are protean. They range from mild personality changes and learning difficulties to profound mental retardation, gross motor deficits, and profound bilateral deafness. A summary of nine retrospective studies of the survivors of bacterial meningitis between 1959 and 1974 is given in Table 1. Together they represent the combined experience of 635 survivors of bacterial meningitis. The methods of classification are not uniform, the consistency of follow-up is variable, and the study populations are different in many respects, including age, organism, and mode of treatment. The striking finding, in view of all this variability, is the remarkable uniformity of results over the years since the introduction of antibiotics. When there are remarkable differences in results, they can usually be attributed to obvious variations in classification, patient selection, and follow-up. For example, Swartz and Dodge's complication rate25 appears significantly less than many of the others; this is attributable to the limited follow-up, relying entirely on reports from other physicians and hospital records. Likewise, Fitzhardinge et al.,26 studying neonatal meningitis, found a much higher incidence of learning disorders and speech and language disorders than was found in studies that included older children and adolescents.
INCIDENCE OF LONG-TERM COMPLICATIONS OF BACTERIAL MENINGITIS
The variation in reported incidence of mental retardation can be attributed to the variable definitions of mental retardation, some using the "standard" definition of an IQ of 69 or less while others used IQ levels of 75 or even 85 to define retardation. Some gave no definition. On the average, however, the incidence of significant mental retardation was estimated at between 5 and 15 per cent, and it was clear from all studies that infants under one year of age, and especially under six months of age, are at the highest risk for severe residual mental deficit, regardless of the organism or method of treatment.2,3125,26
Although mental retardation was invariably studied, only studies since 1962 mention learning difficulties un associ a t ed with evidence of gross mental retardation. As would be expected, when these are examined, high incidences of perceptual, motor, and memory deficits are found; when associated with minor hearing deficits and behavior disorders, these produce a significant incidence of school failure.1
In a more rigorous attempt to evaluate the effects of H. influenzae meningitis, Sell et al.27 did two comparison studies, one using siblings as controls and the second using controls matched for age, sex, social class, and classroom. In the study using sibling controls, 86 postmeningitic children were compared with 97 siblings, using the Wechsler Intelligence Scale for Children. The mean IQ of the postmeningitic children was 86, compared to 97 in siblings - a significant difference (P= <0.05). The second study compared 25 postmeningitic children with 25 matched controls using the Illinois Test of Psycholinguistic Abilities, the Frostig Test of Visual Perception, and the Peabody Picture Vocabulary Test. It showed significant differences between the postmeningitic children on the Illinois Test of Psycholinguistic Abilities and the Peabody Picture Vocabulary Test. These studies were done to document that the deficits noted were related to the meningitis and not to extraneous variables, such as socioeconomic class. The findings make previously reported estimates of the effects of this disease on global functioning more believable. The only way to precisely define the effects of meningitis on intellectual abilities is to have accurate before and after measures on the patients themselves. This would require largescale population studies, which are probably not feasible.
Severe to profound bilateral sensorineural hearing loss occurs in 2 to 6 per cent of postmeningitic children, whereas unilateral or milder hearing loss is evident in 5 to 10 per cent of children following meningitis. While the profound nerve deafness can always be attributed to the meningitis or treatment, the less severe hearing loss is often related to recurrent otitis media. In view of the frequency of deafness following bacterial meningitis, each child should be carefully examined clinically and with audiograms as soon as possible after recovery. This procedure will ensure that the hearing loss is discovered at the earliest possible time and that hearing aids (if indicated) and appropriate educational efforts can be instituted.
The significance of deafness in this population was well documented by Vernon,5 in studies on children in schools for the deaf. Children with deafness due to meningitis make up between 7 and 10 per cent of children in schools for the deaf. Although previous studies reported that the mean age at onset of deafness due to meningitis was in late childhood, Vernon's report indicates that the age has been lowered to between 12 and 20 months. This younger, so-called prelingual age group has a much greater chance of never acquiring speech.
In young infants and children, the combination of deafness and vestibular pathology produces delayed and ataxic walking and delayed language acquisition, which can mimic mental retardation. Great care must be taken not to institutionalize such a child until an accurate measure of his intellectual abilities can be made and attempts have been made at stimulation and education.
Even more disturbing is Vernon's finding5 that handicapping conditions tend to cluster in the more severely affected child. A combination of handicaps - including aphasia, mental retardation, emotional disturbance, and motor deficits - was present in 38 per cent of the postmeningitic deaf children he studied. In addition, even mild depression of intellectual capacity (e.g., IQ <90) or deficits in isolated areas have a more devastating effect on the deaf child, making it less likely that he will be able to achieve even elementary educational level. Handicapping conditions in a child who has recovered from bacterial meningitis present a challenge to educators and members of rehabilitative teams who deal with these children.
Recurrent seizures, both partial and generalized, occur in 4 to 6 per cent of the survivors of bacterial meningitis3'26'29 - much less frequently than they occur during the acute illness.25 Standard anticonvulsant management using phenobarbital, phenytoin, or, if necessary, other anticonvulsants usually suffices to control the seizures. Little information is available as to the relationship between seizures occurring during the acute illness and those occurring on a chronic basis, although it has been noted that there is a relationship between the frequency, severity, and duration of seizures during acute bacterial meningitis and ultimate outcome in both mortality and morbidity. This suggests that seizures occurring during acute bacterial meningitis are an indication of the severity of the initial insult.
Hydrocephalus occurs in 2 to 3 per cent of children following bacterial meningitis,3,30 again pointing to the need for careful followup of all children after their recovery from this disorder. Signs of increasing intracranial pressure and rapidly enlarging head circumference strongly suggest the occurrence of obstruction of either the absorption or flow of cerebrospinal fluid. These signs and symptoms should prompt immediate investigation with computerized axial tomography or, if necessary, pneumoencephalography. On the demonstration of either communicating or noncommunicating hydrocephalus, an appropriate shunting procedure should be performed to prevent any further damage. Medical management using either diuretics (Diamox,® Isosorbide®) or compressive head wrappings has not proved helpful.
Each child who recovers from a CNS infection must be considered individually in terms of what single handicap or combination of handicaps he has, and a plan of management must be formulated. An ideal approach is outlined in Figure 1. This plan often requires the services of a number of skilled practitioners, including the pediatrician, neurologist, psychiatrist, physiatrist, speech and hearing specialist, psychologist, and educators. The coordination of such a plan of management (the responsibility of the primary-care physician) is often time consuming and frustrating, but if done well, it can be rewarding for the patient.* Important elements in the planning must include a clear-cut picture of the nature and severity of each handicap, its effect on the patient and his family, and its interaction with other handicapping conditions. Early identification of problems is important from the point of view both of preventing further disability (as in the case of hearing loss, hydrocephalus, and learning disorders) and of providing appropriate physical and psychologic support to the patient and his family.
In order to facilitate early identification of problems that may result from CNS infections, regular follow-up - in a search for behavioral, developmental, and language abnormalities - should accompany the recommended head-circumference measurements and hearing tests. If abnormality is suspected, prompt referral for psychologic testing, speech and language evaluations and treatment, or psychiatric evaluations should be instituted. Children with motor deficits complicating their recovery may benefit from physical therapy or carefully selected orthopedic surgical procedures.
There is controversy as to the effectiveness of some intervention procedures, especially in the area of "infant stimulation" and physical training.32,33 It is clear that a dead neuron will not recover, but it is not clear that in a developing and somewhat plastic organism methods of adaptation may not be used to compensate for what might otherwise be devastating impediments to learning and socialization. If no such adaptations are possible, identification of disabilities will at least relieve some of the psychologic burden imposed by our competitive society.
Figure 1. Management plan for follow-up of central nervous system infections.
Recent reviews of education for the retarded and programs of cognitive and motor stimulation34,35 point out the need for flexibility in our approach to children with handicaps as well as the need for controlled, prospective longitudinal studies of various proposed methods of stimulation and education. The optimal timing and nature of such intervention must be determined. For example, it has been suggested that the quality of the mother-child interaction between the age of one and three years is a critical determinant of developmental outcome. Does motor training enhance the overall developmental potential of the child with cerebral palsy, or is the improvement often seen related to interactional and maturational variables?32-34
Answers to questions such as these will help determine the priorities for rehabilitative, educational, and social support for children with handicaps that result from nervoussystem infections or other causes. However, rehabilitation in whatever form is expensive and time consuming. A more efficient approach is prevention through immunization, as is proposed for different forms of bacterial meningitis and has proved so successful with poliomyelitis and rubella.
1. Kresky. B., Buchbinder, S., and Greenberg, I. M. The incidence of neurologic residua in children after recovery from bacteria) meningitis. Arch. Pediatr. 79 (1962). 63.
2. Sell. S., Merrill, R, E-, Doyne. E., and Zimsky, E. Long-term sequelae of Hemophilus influenzae meningitis. Pediatrics 49 (1972), 206.
3. Sproles, E. T., Ill, Azerrad, J., Williamson, C., and Merrill, R. E. Meningitis due to Hemophilus influenzae: Long-term sequelae. Pediatrics 75 (1969). 782.
4. Recent Advances. Publication No. (NIH) 75-3, National Institutes of Health, U.S. Public Health Service. Department of Health, Education, and Welfare. 1975, p. 45.
5. Vernon, M. Meningitis and deafness. Laryngoscope 77 (1967), 1856.
6. Desmond, M., et al. Congenital rubella encephalitis. J. Pediatr. 71 (1967), 311.
7. Macfarlane, D., Boyd. R.. Dodrile. C., and Tufts, E. Intrauterine rubella, head size and intellect. Pediatrics 55 (1975), 797.
8. Cooper, L, et al. Rubella, clinical manifestations and management. Am. J. Dis. Child. 118 (1969), 18.
9. Hanshaw, J. Cytomegalovirus infection and cerebral dysfunction. Hasp. Practice (Sept.. 1970), 111.
10. Hanshaw, J.. et al. School failure and deafness after "silent" congenital cytomegabvirus infection . N. Engt. J. Med. 295 (1976), 468.
11. Eichenwald. H. F. Human Toxoplasmosis: Proceedings of the Conference on Clinical Aspects and Diagnostic Problems of Toxoptasmosis in Pediatrics. Baft inore: The Williams & Wilkins Company, 1956.
12. Hallgren, B., and Hallström. E. Congenital syphilis; a follow-up study with reference to mental abnormalities. Psychiatr. Neurol. (Suppl. 93, 1954), 1.
13. Johnson, K. J., Rosenthal, M. S., and Lemer P. I. Herpes simplex encephalitis: The course of five virologically proven cases. Arch. Neurol. 27 (1972), 103.
14. Sells, C., Carpenter, R.. and Ray, G. Sequelae of central nervous system enterovirus infections. W. Eng. J. Mod. 293 (1975), 1.
15. Palmer, R., and Finley. K. Sequelae of encephalitis: Report of a study after the California epidemic. Calif. Med. 84 (1956), 98.
16. Rosenberger, P. B. Editorial: Infectious disease and the immature brain. N. Engl. J. Med. 293 (1975). 39.
17. Purpura. D. P. Dendritic spine "dysgenesis" and mental retardation. Scence 186 (1974). 1126.
18. Freeman, J. M. The clinical spectrum and early diagnosis of Dawson's encephalitis. Pediatrics 75 (1969), 590.
19. Townsend. J., Barringer, R,. and Wolinsky, J. Progressive rubella panencephalitis. N. Engl. J. Med. 292 (1975), 990.
20. Townsend, J., Wolinsky, J., and Barringer, R. The neuropathol ogy ol progressive rubella panencephaltts of late onset. Brain 99 (1976), 81-90.
21. Rosenblum, M. J., Masland, R. L, and Harrell. G. T. Residual eftects of rickettsial disease on the central nervous system. Arch. Intern. Med. 90 (1952). 444.
22. Berman, P. H., and Banker, B. Neonatal meningitis: A clinical and pathological study of 29 cases. Pediatrics 38 (1 966), 6.
23. Smith, J. F., and Landing, B. H. Mechanisms of brain damage in Hemophilus influenzae meningitis. J. Neuropaffiol. Exp. Neurol. 79 (1960). 248.
24. lgarashi, M., and Schuvecht, H. Pneumococcic otitis media, meningitis and labyrinthes. Arch. Otolaryngol. 76 (1962), 126.
25. Swartz, M., and Dodge. P. Bacterial meningitis: A review of selected aspects. N. Engl. J. Med. 272 (1965). 725.
26. Fitzhardinge. P., et al. Long-term sequelae of neonatal meningitis. Dev. Med. Child Neurol. 16 (1974). 3.
27. Sell, S., Warren, W., Pate, J.. and Doyne E., Psychological sequelae to bacterial meningitis: Two controlled studies. Pediatrics 49 (1972). 212.
28. Bbor, B., Grant, R. S.. and Tabris, J. Long-term effects of bacterial meningitis. J.A.M.A. 142 (1950), 241.
29. Wolff, 0.. and Small, W. C. Sequelae of Hemophilus influenzae meningitis. Arch. Dis. Child. 27 (1952), 302.
30. Bergstrand, C. G.. Fahlön, T., and Thilén, A. A follow-up study of children treated for acute purulent meningitis. Acia Paediatr. 46 (1957), 10.
31. Lorber, J. Long-term results in 100 children surviving tuberculous meningitis. Pediatrics 28 (1961), 778.
32. Forness, S. R. Education for retarded children. Am. J. Dis. Child. 127 (1 974), 237.
33. Marquis, P. Cognitive stimulation. Am. J. Dis. Chid. 130 (1976). 410.
34. Bleck, E. E. Locomotor prognosis in cerebral palsy. Dev. Med. Child Neurol. 17(1975), 18.
35. Scherzer, A. L., Mike. V., and llson, J. Physical therapy as a determinant of change in the cerebral palsied infant. Pediatrics 58 (1976), 47.
INCIDENCE OF LONG-TERM COMPLICATIONS OF BACTERIAL MENINGITIS