THE JOURNAL OF PEDIATRICS SEPTEMBER 1967 Volume 71 Number 3 Congenital rubella encephalitis Course and early sequelae Neurological abnormalities were noted at some time between birth and 18 months of age in 8l of 100 patients with congenital rubella infection. These included lethargy, full fontanel, irritability, and increased concentration of protein and persistence of virus in the cerebrospinal fluid. Of the 64 survivors 44 had a wide range of neurological abnormalities at 18 months of age including motor paresis, restlessness, motor mannerisms, and developmental delay. Retardation in growth, particularly of the head, was still manifest at 18 months. Pathological changes in central nervous system structures included leptomeningitis, vascuIitis, and multifocal areas of parenchymal necrosis and perivascular calcification. Murdina M. Desmond, M.D., Geraldine S. Wilson, M.D., Joseph L. Melnick, Ph.D., Don B. Singer, M.D., Thomas E. Zion, M.D., Arnold J. Rudolph, M.D., Rebecca G. Pineda, M.D.,* Mir-Hashem Ziai, M.D.,* and Russell J. Blattner, M.D. HOUSTON~ TEXAS From the Departments of Pediatrics, Virology and Epidemiology, Pathology, and Neurology, Baylor University College of Medicine, the Nursery Service of Jefferson Davis Hospital, the Clinical Research Center, and the Junior League Outpatient Department of Texas Children's Hospital. Supported by the following grants: Children's Bureau Project No. 432; John A. Hartford Foundation, Inc.; Public Health Service Research Grant No. FRO0188 from the General Clinical Research Center Branch; Public Health Service Research Grants AI-05382 and AI-02963 from the National Institute [or Allergy and Infectious Diseases; Farrish Fund; Rubella Research Fund, Texas Children's Hospital; General Research Support Grant FR 05425; Common Research Computer Facility, United States Public Health Service Grant No. FR 00254. XFellow in Neonatology. Vol. 71, No. 3, pp. 311-33l 3 12 Desmond et al. G R z o o 1 IN 1941 and Swan and associates 2 in 1943 reported the now well-established association between rubella infection contracted by the mother during early gestation and central nervous system (CNS) disease in the offspring. Congenital rubella is now known to be a highly contagious viral disease which involves many systems including the CNS. a, ~ Leptomeningitis and encephalitis have been described in the fetus and young infant.3, 5-7 Rubella virus has been isolated from cerebrospinal fluid (CSF) and cerebral tissues. 7-9 Recently, Rorke and Spiro 1~ reported extensive degenerative changes in cerebral vessels in the brains of 9 children dying with the congenital rubella syndrome. Vascular damage was associated with multifocal necrosis localized in white matter and grey nuclei. Myelinization was retarded. Following the widespread epidemic of rubella which occurred in the United States in 1964 to 1965, a number of infants with congenital rubella were born in the Houston area. A ward and clinic were set up to follow the early course of infants with congenital rubella and to detect problems arising in infants born to mothers with a history of rubella during early gestation. The present report is concerned with the natural history of rubella encephalitis as recorded during the course of repeated examinations of 100 infants during the first 18 months of life. This study is largely one of affected infants since ninety of the one hundred had manifestations of transplacental rubella observed either at birth or during early infancy. PATIENT POPULATION AND BIRTH STATUS Although 135 patients have been followed, only the first 100 patients considered to have proved rubella are analyzed in this report. The remaining 35 patients either were not considered to have had proved rubella or were enrolled after 18 months of age. All of the 100 had laboratory evidence of rubella infection (virus isolation or significant antibody) or a positive history of rubella infection in the mother during early pregnancy. The Journal of Pediatrics September 1967 Race and sex. Of the patients 63 were Caucasian and 37 were Negro. Male infants predominated over female (59 to 41); 1 pair of twins (1 male, 1 female) were included in the series. Economic clinical status. These patients were referred by various groups (citycounty hospital--31 patients, part-pay clinics--28, and by private physicians--41). Age at first examination. There were 46 patients who were first seen during the neonatal period (22 during the first 48 hours); 42 were enrolled between 2 and 6 months, 10 between 7 and 12 months, and 2 after 12 months of age. History of rubella during pregnancy. Of the mothers, 10 gave no history, of rubella exposure or rubella infection during the first 16 weeks of pregnancy; 10 were exposed to rubella, but did not develop a clinical infection; 47 had an illness during early pregnancy compatible with rubella; and 32 had a physician-diagnosed infection. ( 1 history was not obtainable, since the mother was mentally retarded). Gestational age. The mean gestational age was 39 weeks. Gestational age was unknown in 7 infants, was 36 weeks or less in 8, 37 to 41 weeks in 77, and 42 weeks or over in 8. Birth weight and intrauterine growth. Of the 100 infants, 38 weighed over 2,500 grams at birth, and 62 weighed 2,500 grams or less. The mean birth weight in male infants was 2,433 grams +_ 611; in female infants it was 2,410 grams +_ 587. Intrauterine growth. Birth weights for gestational age were compared with the standards of Gruenwald 11 and Lubchenco and colleagues22 Forty (43.5 per cent) of 92 infants of known gestational age had birth weights over 2 standard deviations below that expected for gestational age, i.e., significant intrauterine growth retardation by Gruenwald's criteria. According to the standards of Lubchenco, 1~ 59 per cent of the infants were below the tenth percentile in weight, 24 per cent in length, and 39 per cent in fronto-occipital circumference (FOC~). Birth status. The status of the infant at ~FOC ~_ fronto-occipital circumference of head. Volume 71 Number 3 Rubella encephalitis 3 13 40 if) I..-. z IRRITABILITY :32 ~/ ' LIJ B I-- , / \ \ "\ i O ~-'-, ,/ f ~ / f INTERMITTENT HEAD RETRACTION AND ~BACK ARCHING 0NTANE / / ," I 0 LrE~'.'~,,OPISTHOTONUSAT i i 3 6 AGE ~::~r".-..-,, 9 I I 12 15 REST I 18 IN MONTHS Fig. 1. Course of Rubella Encephalitis in 69 infants followed periodically to 18 months. birth is given in Table I. Ten infants had no evidence of clinical disease; 34 had thrombocytopenia or purpura, and the remaining 56 were seen because of congenital anomalies attributable to rubella or because of illness in the infant coupled with a history of rubella infection in the mother. Only 20 of the above 56 were diagnosed as congenital rubella syndrome during the birth hospitalization. COURSE OF RUBELLA ENCEPHALITIS Although symptomatology referable to the CNS was noted at some point between birth and 12 months of age in 81 patients of the original 100, the pattern of neurological involvement in relationship to age could be described only in the 69 who were consistently followed in the clinic or hospital (Fig. 1). No neurological abnormalities were noted in 7 of the 100 during the first year. Other phases of generalized rubella infection (congestive heart failure, pneumonitis, hepatitis, diarrhea, and otitis) predominated until the time of death in 11 profoundly ill patients. Clinical information relative to the early months was incomplete in t3 patients. The progression of abnormal neurological symptomatology in the 69 well-studied patients is given in Fig. 1. The symptomatology followed one of three general patterns, designated as Types A, B, and C (Table II). Type A. This was most frequently encountered. It occurred in mild or incomplete form in 21 infants and severe form r in 28. Characteristically, these infants were lethargic, hypotonic, inactive and had a large full anterior fontanel either at birth or during the first days or weeks after birth. Irritability gradually overshadowed the early lethargy. Irritability (or in many patients, agitation) was the most prominent finding between 1 and 4 months of age. These infants exhibited restlessness, constant motion, frequent crying, disturbed sleep, excessive sucking, variable reflexes, sweating, vasomotor instability, and a general overreaction to stimuli. Intense photophobia was not uncommon. Although feeding was sometimes difficult, owing to vomiting and incoordinafion of sucking and swallowing, the majority took more than the customary amount of formula. When not feeding they were crying, rooting, or sucking their fists. While crying, they often extended the head and lower extremities. The arms were usually flexed at the elbow, and the hands tightly listed. Transient asymmetries of tone or reflexes were not infrequent. Toes were maintained for the most part either in hyperextension or in exaggerated toe grasp. ~'Infants were considered to be severe when they manifested continuous irritability together with tone disturbances or when irritability was followed by opisthotonus at rest. 3 14 Desmond et aL The Journal o[ Pediatrics September 1967 Table I. The birth status of 100 infants with a history of maternal Seen during neonatal period No. Considered ill at birth rubella or congenital Viral isolation Any source [ CSF Uninvolved at birth (followed because of maternal history only) 10 9 (90%) 0 (0%) 6 (60%) 2 (20%) Rubella syndrome with thrombocytopenia or purpura 34 28 (82%) 34 ( 100% ) 24/32t (75%) 13/29~ (45%) Rubella syndrome without thrombocytopenia or purpura 56 9 ( 16% ) 20 (36%) 25 (45%) 13/53~ (25%) Totals 100 46 54 55 28 "XPercentages are based on the total number of patients in each category. "~Number tested, Table II. T h e course of rubella encephalitis related to viral isolation, clinical findings, laboratory Neurological findings Viral isolation No. o[ Neurological course No neuroIogic abnormalities in[ants 7 Any source incl. CSF CSF Full [ontanel 0 Increased spinal fluid protein 0 Seizures 1 Head retraction and back arching 0 4 1 (57%) (14%) (0%) (0%) (14%) (0%) 20 10 (50%) 5 (25%) '9 (45%) 8 (40%) 1 (5%) 12 (60%) 31 21 (68%) 11 (35%) 22 (71%) i6 (52%) I0 (32%) 22 (71%) 11 5 (45%) 2 (18%) 3 (27%) 3 (27%) 4 (36%) 3 (27%) 5 (71%) 3 (43%) 4 (57%) 3 (43%) 6 (86%) 2 (29%) 6/10t (60%) 2/6t (33%) 6 (55%) 2/6* (33%) 1 (9%) (9%) 4/11t (36%) 4/9t (44%) 1 (8%) 1/9" (11%) 4 (31%) 4 (31%) Abnormal neurologic course A. Early lethargy followed by irritability, tone disturbances, opisthotonus and motor delay 1. Mild 2. Severe B. Early developmental delay and tone disturbances (primarily hypotonia) C. Abrupt onset with convulsions or meningitic-like picture Other mani[estations o[ rubella syndrome predominating until death 11 In[ormation incomplete during first six months 13 Totals 100 55 ~'Outcome groups 3 and 4. "~Number patients who had a lumbar puncture performed. 28 45 33 27 I 44 Volume 71 Number 3 R u b e l l a encephalitis 3 15 rubella syndrome ~ Neuromotor Died be[ore I8 too. outcome at 18 months Lost to study Followed to 18 months Sensory impairment diagnosed by 18 too. Normal Group I Minimal Group 2 Severe Group 3 + 4 Visual I Hearing lo~ 0 (0%) 1 (10%) 2/4f (5O%) 0 (0%) (60%) 4 (40%) 4 (40%) 0 (0%) 13 (38%) 6 (18%) 15 (44%) (9%) 3 4 (12%) 8 (24%) 24 (71%) 6/15f (40%) 7 (13%) 4 (7%) 45 (80%) 13 (23%) 10 (18%) 22 (38%) 40 (71%) 21/45 t (47%) 20 6 16 64 20 14 30 65 29/64f findings, and outcome at 18 months Outcome Sustained opisthotonus 0 H~perpigmentation skin Deaths Lost to study Extent of neuromotor impairment at 18 months None [ Mild Severe* Deaths plus severe ~euroTTtotor impairment at 18 months 1 0 2 5 0 (0%) (14%) (0% (29%) (71%) (0% 0 (0%) 0 (0%) 8 (40%) 1 (5% 3 (15%) 9 (45%) 4 (20% 3 (15%) 17 (55%) 16 (52%) 5 (16% 3 (lO%) 3 i0%) 6 (19% 14 (45%) (61%) 0 (0%) 6 (55%) 1 (9% 2 (18%) 0 (0%) 3 (27% 5 (45%) (55%) 2 (20%) 3 (43%) 2 (29% 1 (0%) 14%) (14% 3 (43%) (71%) 0 (0%) (9%) 1 11 (100% 0 (0%) 0 (0%) 0 (0% 0 (0%) (100%) 0 1 0 (0%) (8%) (0% 19 36 20 0 1 6 2 (46%) (16%) 16 20 0 (0%) 14 5 (38%) 30 0 (0%) 4 (20%) 10 6 5 11 5 (38%) 50 3 16 Desmond et al. The Journal o[ Pediatrics September 1967 two months. T h e restlessness preceding or accompanying congestive failure was associated with changes in the quality of heart sounds, tachypnea, and tachycardia. I n encephalitis without superimposed congestive failure, respiratory rates were irregular but not consistently increased.) Although the majority were hypotonic, Weight gain was extremely poor even in the presence of adequate intake. Body temperature tended toward high normal with many brief unexplained periods of fever. At 3 to 4 months the majority of infants had a complete head lag and poor placing-supporting reactions. ( M a n y of these infants also developed congestive failure during the first Heod Circumference in era, 35le~s than .~'percentile for I month 3151- less thon 3~percentile for I month Length in cm. 453000Weight in gin. less thon 3r~percentiJe 2000- CSF Cell for birth Count (mm 3 ) CSF Protein (mg %) CSF Virology 2 14 21 20 182 504 120 20 + + + - 4 + Electroencephalograph Birth I I + + I 2 I t 3 4 Months i 5 I 6 I 7 Fig. 2A. Course of encephalitis in infant with congenital rubella syndrome associated with thrombocytopenia and congenital heart disease (patent ductus arteriosus and patent foramen ovale). The infant died at 7 months. Note peak of spinal fluid protein at 2 months. Fig. 2B. Appearance of same infant at 5 months showing constant opisthotonus and severe growth retardation. At autopsy, this infant had leptomeningitis and widely disseminated areas of parenchymal necrosis and perivascular calcification in cerebral white matter, pons, midbrain and basal ganglia (See Fig. 13). Volume 71 Rubella encephalitis Number 3 hypertonus was also seen in some at an early age. With handling or with change of orientation in space, opisthotonic posturing occurred. In the majority, opisthotonic posturing was transient and appeared only with stimulation. In 12 infants of Type A, it progressed to become true opisthotonus with rigidity (Fig. 2 A and B). On the pull-to-sit maneuver the complete head lag initially present in many of these infants was gradually replaced by an "active" head retraction and back arching. This movement was an outstanding characteristic of these infants lasting in some beyond the first year. All infants classed as type A, severe form, had a marked delay in motor development and little socialization until the phase of excitation had begun to decline. Responses to sound stimuli were frequently inconsistent during periods of intense irritability. Between 6 and 12 months, about half of the children had a striking amelioriation of symptoms and began to make developmental progress. The remainder continued to demonstrate neuromotor impairment. Type B (11 patients). In this group, the predominating picture was that of a small, unreactive "good" baby, usually hypotonic, who failed to progress satisfactorily in weight gain, motor activity and socialization. Infections and feeding problem (poor suck, poor swallow, vomiting, hyperperistalsis) were frequent. The deep tendon reflexes were usually increased. Intermittent opisthotonus, irritability, hyperactivity, and hypertonicity were present in this group as in Type A but tended to appear after six months of age. Improvement occurred in this group usually at 9 to 12 months. Type C (7 patients). In this group, an abnormal neurological course was initiated by the abrupt appearance of convulsions or a meningitis-like picture. In 2, convulsions occurred on the natal day. In the first, convulsions developed following resuscitation. In the second, convulsions associated with flushing of the head, apnea, excessive mucus, and swallowing difficulty were present from birth and continued for three months. 3 17 Two small-term infants (965 and 1191 grams at birth) developed seizures at 2 and 3 days. One had associated hypoglycemia and hypocalcemia and the other hypoglycemia alone. Two infants were considered by their parents to be developing normally until an acute meningitis-like illness occurred at 2 89 and 3 months of age, respectively. Both of these children had hepatitis as well as pleocytosis and increased spinal fluid protein. The seventh infant suffered recurrent infections from birth, but development was normal to 7 months. With the onset of seizures, the infant became hypotonie, and spontaneous vocalization ceased. N E U R O L O G I C A L FINDINGS The findings listed below are discussed in relation to the total group of 100 patients (Tables II, III, IV). Cerebrospinal fluid protein and cell counts. As previously reported, infants with congenital rubella infection demonstrate a moderate increase in spinal fluid protein and a moderate pleocytosis.6, 18, ~4 (Table IV, Fig. 3). In the majority the spinal fluid protein was high at birth diminishing to normal levels after 3 months. In the minority, spinal fluid protein increased after birth to high levels which remained well above normal for a period of months. (The latter pattern was associated with a high mortality rate and Table III. Summary of findings in rubella encephalitis* Symptoms ] Per cent Tone disturbances Head retraction and back arching Bulging anterior fontanel Irritability Vasomotor instability Lethargy Seizures Asymmetry of tone or reflexes Incoordination of sucking or swallowing mechanisms Abnormal cry *Incidence in total group of 100 patients at during the first 18 months, 86 49 45 45 33 28 27 22 15 8 anytime 3 18 Desrnond et al. The Journal o~ Pediatrics September 1967 Table IV. Cerebrospinal fluid protein andcell count Age 1-7 Days 1 Month 2 Months 3 Months 4-6 Months 7-9 Months 10-12 Months 13-18 Months Protein (mgms. %) Number o/ patients tested Median 15 17 15 36 53 32 16 17 98 86 68 51 28 25 27 23 Range 45-548 26-180 11-504 18-480 10-126 8- 76 16- 96 6-130 700 600 Cell count (ce//s per cubic mi//imeter) Median ] Range 2O 21 15 19 10 8 6 4 2-77 2-6O 1-55 1-68 0-80 0-112 1-24 0-52 CSF protein in newborn N Meon infants (Widen) standard deviation [] One above mean (WidelI) 500 400 300 Median CSF protein in imrnolure ~infonfs ( Gyllensw~rd and Molrnstr~m ) 220~ " 200 CSF PROTEIN 180 mgm% .. 'L 160 izo I 140~100 9 8o~,. 60 i 9 ;. 9 9 . i , .,. :. I 9 9 : 9 , $ 9 20 0 2 4 6 8 10 12 4 WEEKS AGE 6 8 tO 12 14 16 18 MONTHS Fig. 3. Levels of protein in cerebrospinal fluid in 100 patients with congenital rubella syndrome. severe neurological abnormality at 18 months. ) Increased spinal fluid protein was defined as 100 mg. per cent during the first 2 months of age, and 50 mg. or higher after 3 months. By these criteria, 33 patients had an increased concentration of spinal fluid protein. Viral isolation and persistence. Rubella virus was isolated from 1 or more sources in 57 patients and from the spinal fluid in 28 patients (29 per cent) (Tables V and VI). It persisted in the cerebrospinal fluid throughout the first year in 9 patients and in one patient throughout 18 months. In the latter, rubella virus was also isolated from middle-ear fluid. A positive isolation of rubella virus from spinal fluid was obtained more frequently in infants with thrombocytopenia at birth (45 per cent), in those with seizures (48 per cent), and in infants who died during the study period (46 per cent). Although virus was isolated from the spinal fluid of 6 of the 20 infants with good outcome, (i.e., no neurological abnormality) at 18 months, all of the "positive" infants Volume 71 Number 3 Rubella encephalitis SEIZURES had residua of rubella, i,e. visual impairment or hearing loss. Rubella virus was isolated from the spinal fluid of 5 of 8 patients (63 per cent) in w h o m the only significant congenital defect at 18 months was hearing impairment. Bulging anterior [ontanel. O f the infants, 45 had a full (but not tense) anterior fontanel, usually in association with a wide open anterior fontanel and separated sagittal and metopic sutures. T h e fullness of the fontanel often appeared first or became more pronounced during the first two weeks of life. T h e peak incidence occurred during the first 3 months. It was present after 6 months in 7 patients and after 9 months was not consistently present in any patient. One or more convulsions were observed in 27 of the 100 infants. Seizures in 2 were considered to be febrile and were not recurrent. Recurring seizures without fever were present in 25. T h e age of onset ranged from 11 minutes after birth to sixteen months. I n 11 with onset before 3 months, factors other than primary CNS disease were contributory in 7 instances (hypoglycemia, 2; birth asphyxia, 1; hypocalcemia, 1; anoxia associated with pneumonitis; congestive heart failure, 4). I n 14 patients whose seizures began later, convulsions were a reflection of severe CNS disease. C h a r a c t e r of seizure. T h e types of seizure in babies with C N S involvement were as follows: 1. A b r u p t hyperextension of head and trunk, flexion or rigid forward extension of the arms, fisting of the hands, and loss of contact for periods of 10 to 15 seconds. Episodes were fi-equently accompanied by apnea and cyanosis or repetitive, shrill expiratory out-cries. (This general type was encountered most frequently.) 2. Brief loss of contact with fixation of posture and transient myoclonic eye Table V. Isolation of rubella virus from the spinal fluid in relationship to age No. CSF specimens Age in months tested O- 3 4- 6 7- 9 10-12 13-18 Months Months Months Months Months No. positive isolations Per cent positive 25 9 11 5 1 25 15 32 31 7 99 60 34 16 15 3 19 Table VI. Isolation of rubella virus in relation to outcome at 18 months Virus isolated [rom cerebrospinal fluid Virus isolated [rom any source No. Positive No. Tested Per cent Positive No. No. Per cent Patients Positive Tested Positive Total group 57 98 56 28 84 37 14 19 74 6 13 46 7 15 47 2 12 17 36 63 57 20 64 31 10 6 20 13 50 46 6 2 20 13 30 15 9 15 60 5 15 33 11 15 73 7 15 47 Patients who died before 18 months Lost to study before 18 months Patients surviving to 18 months Neurological findings at 18 months 1. No abnormal neurological findings 2. Minimal 3. Severe--improvement 12--18 months 4. Severe--no improvement 12--18 months 320 Desmond et al. The Journal o[ Pediatrics September 1967 movements (this type was seen in infants 9 to 18 months of age). 3. Sudden flushing of the face and head associated with myoclonic eye movement and/or apnea. In one patient, episodes were followed by excessive flow of oral mucus. 4. Abrupt onset of pallor, apnea, and bradycardia lasting 5 to 20 seconds. The electroencephalogram was interpreted as abnormal in 10 of the 27 patients (37 per cent). Rubella virus was cultured from the spinal fluid in 13 (48 per cent) and high spinal fluid protein was noted in 14 (52 per cent). Four (14.8 per cent) expired before 9 months of age and 16 (59.2 per cent) had severe neurological impairment at 18 months. Thus 74 per cent of infants with seizures either expired or had significant residua at 18 months of age. Seizures, therefore, are an ominous prognostic sign. ABNORMAL POSTURES MOVEMENTS AND The following were noted between 9 and 18 months of age: Lateral rotation o[ legs and feet. One of the consequences of prone positioning of hypotonic infants was a lateral rotation of legs and feet similar to that described by Kite. 1~ In prone position, the great toe rested on the surface and the foot was abducted. When the infant was subsequently held in supported standing, the legs were laterally rotated at hips and knees and the toes pointed outward about 90 degrees. With the development of lower extremity spasticity this position was perpetuated (Fig. 4). Sustained head retraction. After some of the children had achieved head control in sitting or supported sitting they were apt to retract the head slowly, and to maintain it in this position with no apparent discomfort (Fig. 5). Infants with impaired vision not infrequently hyperextended the head to gaze at light, objects or persons, in lieu of turning the body. In early months (1 to 9) mothers often reported that is ,,as difficult to hold the baby over the shoulder or supine in their arms because of head retraction and arching of the back. The majority did not appear to be comfortable in a supine position. Fig. 4. Lower extremities of infant with congenital rubella syndrome at 18 months. Note the spasticity, lateral rotation of leg and foot with abduction of big toe. Fig. 5. Hyperextension of the head in supported standing. Infant has bilateral cataracts, surgically corrected. Volume 71 Number 3 Supine crawling in opisthotonic position ("wrestlers a'rch position"). Four severely involved infants developed a unique tripod posture at the time crawling would be expected to occur in the physiological motor sequence (Fig. 6). The body, in supine position, was supported above the surface by the hyperextended head and the heels. By symmetrically or alternately lifting the feet, the infant moved in a cephalad direction. Two transferred objects from hand to hand while in this position. Two showed circular areas of baldness as a result of friction between scalp and floor. Three of these infants have visual impairment, two are suspected of hearing loss, and one has no vestibular response to rotation. Sitting in "reversed tailor" position. Almost all infants sat with knees posteriorly flexed and feet everted. This position is not abnormal in healthy infants. However, it was consistently seen in infants with congenital rubella. This type of sitting also accentuated the lateral rotation of legs and feet. Episodic movements of lower extremities. Three infants had outbursts of alternate "bicycling" movements or symmetrical raising and lowering of both extremities at the hip joint while lying in the supine position. These episodes lasted 1 to 2 minutes, and ceased abruptly. Bent-over stance. Standing with body completely bent over and crown of head Fig. 6. Supine crawling in opisthotonic position in 10-month-old infant with congenital rubella. Photograph by courtesy of Dr. Meeker of Port Arthur, Texas. Rubella encephalitis 321 resting on the floor was a preferred position in a few infants. Toe walking. Walking on flexed toes or the ball of the foot with heels lifted was the most common mode of early walking in the majority of children and persisted in some to 18 months. Movements associated with sensory losses. Rocking of the body and head banging were frequent in infants with hearing loss or combined visual and hearing loss. Prolonged hand regard, waving of spread fingers in front of the eyes, and intentional poking of fingers into the eyes appeared to be associated with eye lesions. ELECTROENCEPHALOGRAPHIC TRACINGS Electroencephalograms were obtained when possible at 1, 3, 6, 12, and 18 months. A total of 221 tracings were obtained in 83 patients. Thirty of the 83 (36 per cent) had one or more abnormal tracings. The majority of abnormal tracings were obtained during the early months of the first yem (Table VII). Abnormalities included high voltage sharp wave transients, rhythmic high voltage 1 to 2/second waves in frontal areas, and characteristics of immaturity in infants full term by gestation. SKIN MANIFESTATIONS (Table II) Hyperpigmentation. Deposits of dark brown pigment about the navel, forehead, cheeks, and at sites of previous skin breaks were seen in 39 patients, both Caucas2an and Negro. Lesions were most prominent between 3 and 6 months of age, after which they gradually faded. Seborrhea, involving the cheeks, forehead, and body generally was seen in 38 infants and eczema in 8. Peak incidence occurred between 3 and 9 months. One infant, at 18 months, had well-developed acne with comedones. Three infants had recurrent urticaria. Causal factors were not known. Vasomotor instability was present in 31. Severely involved infants had poor periph- 322 Desmond et al. The Journal of Pediatrics September 1967 eral circulation with generalized mottling, a slate-blue coloring of dependent extremities, and a vivid red flush of ears, cheeks, finger tips, and toes when the infant was warm (Fig. 7). OUTCOME AT lesion or a hearing loss, and 6 had had virus isolated from the spinal fluid.) Group 2. Minimal neuromotor impairment (14 patients). These children, although slow, were standing or walking with support at 18 months. All were communicating with persons and exploiting objects in the environment, although only 2 were without visual or auditory impairment. Findings in this group included: hyperactivity and restlessness (8), monoparesis (1), hemiparesis (1), incoordinated hand movement (2), ataxia (1), toe walking (4), strabismus (2), abnormal cry (3), stridor (1), increased deep tendon reflexes (1), and constant drooling (1). Group 3. Severe neuromotor impairment; with improvement between 12 and 18 months o[ age (I5 patients). All these children had persisting motor problems. These 18 M O N T H S Neuromotor. Of the original group of 100, 20 died and 16 were lost to study before 18 months of age. The remaining 64 were evaluated at 18 months of age. The infants were grouped into 4 categories (Tables VIII and IX) on the basis of the severity of neuromotor involvement at this age. Group 1. No neuromotor impairment at 18 months (20 patients). These children were walking alone and functioned normally in areas unaffected by sensory handicap. (All but 3, however, had either a visual Table VII. Summary of EEG readings in congenital rubella syndrome 1 1 Month or less 2 Months 3-5 Months 6-12 Months I8 Months Total tested Read 32 20 30 117 20 as 23 11 3 7 2 abnormal (72%) (55%) (10%) (6%) (10%) Equivocal Within normal variation 1 1 3 l 2 8 8 24 21 16 Table VIII. Neuromotor impairment, FOC, and sensory handicaps in survivors at 18 month Hearing losses Severity of neuromotor impairment None evident No. of patients 20 Minimal impairment 14 Severe involvement with improvement between 12 and 18 months 15 Severe involvement with minimal progress, no progress, or deterioration between 12 and 18 months 15 Totals 64 FOC and FOC below length below No hearing loss 3rd percentile 3rd percentile Definite hearing loss 5 9 (70%) (25%) (45%) (5o%) 10 (71%) 3 (21%) 2 (14%) 11 (79%) 14 14 (93%) 14 (93%) 52 (81%) 6 (40%) 9 (60%) 23 (36%) 10 5 6 (33%) (40%) 2 13%) 2 (13%) 18 28%) 29 (45%) Volume 71 Number 3 Rubella encephalitis included: tetraparesis (6), hemiparesis (1), monoparesis ( 1 ), motor delay with hypotonia (3), and intermittent hypertonicity (4). Additional findings are given in Table IX. They are similar to those of group 4, except that all patients in group 3 had some communication with parents and awareness of the environment. All had visual, auditory, or speech handicaps. Group 4. Severe neuromotor impairment without significant improvement between 12 and 18 months (15 patients). These children were severely impaired and showed either minimal improvement, no improvement, or apparent regression between 12 and 18 months. All had sensory handicaps. Fourteen have tetraparesis (with spasticity, hypotonia, or athetosis) and 1 severe motor delay with mild spasticity of lower extremities. Additional findings are given in Table IX. Group 4 includes 8 infants who appear to be isolated, autistic, and out of communication with the environment. Eleven (including the 8 above) have failed to make progress in adaptive behavior, and therefore, must be considered to be mentally retarded at the age of 18 months. Initial symptomatology related to outcome (Table I). Six of the 10 infants con- 323 sidered uninvolved at birth were lost to study. Of the 4 continuing in the study, 2 showed a mild form of course A but were considered normal at 1 year; 2 of the 4 have a hearing loss, and 1 has chorioretinitis. Infants with thrombocytopenia had the highest mortality rate (38 per cent). However, the percentage of severe neuromotor disability at 18 months, and the percentage of diagnosed hearing losses were approximately the same in infants with or without thrombocytopenia or purpura. Of the entire group, approximately half the survivors have a diagnosed hearing loss and half have severe neurological disabilities. These groups do not overlap greatly (Table V I I I ) . (The percentages for hearing loss are probably low because of difficulties in testing infants with severe neurological disability. ) Eleetroencephalographic tracings. A high percentage of abnormal electroencephalograms (EEG) (8 of 9 or 90 per cent) was obtained in infants who died and in infants with cataracts (15 of 27 or 55 per cent). A low percentage (3 o{ 16 or 19 per cent) was noted in infants with hearing loss but without cataracts. The percentage of abnormal tracings in infants with seizures (37 per cent) was similar to that of the total group (36 per cent). examination and speech Poor speech and inconstant response to sound 1 (5%) 1 Bilateral cataract 1 (5%) 1 Ocular manifestations Unilateral cataract Glaucoma 3 (15%) (0%) 8 4 (40%) (20%) 6 2 (7%) (29%) (0%) (43%) (14%) 4 (27%) 8 (53%) 4 (27%) 0 (0%) 4 (27%) 0 (0%) 11 (73%) (53%) (7%) (7%) (13%) (0%) 17 (27%) 18 (28%) 12 (19%) I (2%) 20 (31%) 6 (9%) 1 0 Chorio-retinitis (7%) 8 4 0 No hearing, speech or visual problem 1 2 0 3 24 Desmond et al. The Journal o[ Pediatrics September 1967 T a b l e I X . S u m m a r y of neurological findings in 64 infants with rubella syndrome at the 18 m o n t h e x a m i n a t i o n I No. o/ ]patients Most advanced gross motor achievement noted at the 18 month examination ~ Walking alone Without motor deficit With motor deficit Walking with support Standing with support Sitting alone or in tripod position Supported sitting Head control only No voluntary control of head, trunk, or lower extremities Total patients Predominant persisting motor deficitt$ Tetraparesis With general spasticity With hypotonia With spasticity of lower extremities With athetosis With asymmetric involvement of upper extremities Paraparesis With spasticity With hypotonia Hemiparesis Monoparesis Severe Motor Delay With hypotonia With intermittent hypertonus Total patients Other abnormalities Hyperactivity and restlessness Hypotonic shoulder girdle Lateral rotation of feet Incoordination of swallowing mechanism Strabismus (in infants without cataracts) Head retraction and back arching Hypertonicity on stimulation Stereotyped movements Abno.rmal associated movements Tremors Curls marmorata Apparent unawareness of environment Mental retardation (no progress in adaptive behavior) 32 20 12 11 4 6 1 2 7 64 20 4 9 4 1 1 2 I 1 ~P <2 0.05. 2 2 6 5 1 32 16 16 14 8 7 9 8 12 3 2 4 8 11 "~Gross motor abillty at 18 months; twenty of the 64 infants had no neurological abnormalities at 18 months and are listed here only. ~'Predomirtating motor deficit. Other abnormalities are listed in third section of table, All patients w h h motor deficits listed in third section are also included in this section. $Classification of Paine and Oppd. ~"1 Electroencephalograms were taken in 20 survivors at 18 months of age. O f these, 16 were interpreted as n o r m a l ; 10 of the 16 infants with n o r m a l tracings h a d severe (group, 3 a n d 4) neurological disability. T h u s the status of the E E G t r a c i n g at 18 months does not correlate with neurological status at 18 months. However, the reading o~ electroencephalograms taken before 6 months of age m a y relate m o r e closely to the 18 m o n t h outcome. Young infants with a b n o r m a l electroencephalograms h a d a higher m o r t a l i t y a n d a higher percentage of neurological disability at 18 months than did infants with n o r m a l tracings t h r o u g h o u t ( T a b l e X ) . S o m a t i c growth. Poor somatic g r o w t h continued t h r o u g h o u t 18 m o n t h s (Figs. 8 and 9). M a l e infants w i t h no neurological abnormalities at 18 months were signific a n t l y l a r g e r (height, weight, a n d F O C ) t h a n m a l e infants with a poor outcome at 18 m o n t h s ( G r o u p 1 vs. G r o u p 4~). Differences were not significant in female infants. Fig. '7. Cutis marmorata in 10-month-old infant with congenital rubella syndrome and severe neurological impairment at 18 months. Twin sibling considered normal to I2 months when hearing loss was diagnosed. FOC of patient at 18 months 43 cm.; FOC of twin 43.3 cm. Volume 71 Number 3 Rubella encephalitis 325 Table X. Outcome of infants with one or more abnormal electroencephalograms before 6 months of age in comparison with that of infants with normal electroencephalograms before 6 months of age. I EEG's all normal I EEG's one or more abnormal Suru~vo?'s 18 Month Neurological Evaluation No neurological impairment Mild impairment Severe with improvement 12-18 months Severe, no improvement 12-18 months 3} 3 6 } 34.6% 4 6 } 67% 3 2 5 33% 9 0 Died be[ore 18 months 90 50 22 65.4% I0 3 20 18 96i 90 92+ 50 88i ,o 84 16 80 76 14 72 Cm. Kg. 12 / IO 9 68 64 IIII ~ Yll ~,,( --- Good . e . , o m o , o r o~=ome Severe 60 56 61 9 t. Expired i 52 WEIGHT neuromotor abnormality ( no improvement 12-18mo.) LENGTH 48 4 84 44 2 I 9 , 0 , I 6 12 MONTHS , I , 40 18 I 0 1 6 I , I 12 18 MONTHS , I 24 , I 30 Fig. 8. Weight and length in infants with congenital rubella compared with standards for healthy ehildrenY6 Data equalized for sex distribution. Note severe growth retardation in infants who did not survive. Of the 64 survivors followed to 18 months 22 (34 per cent) were below the third percentile for length, weight, and FOC. However, the number of infants with a small FOC at 18 months (52 or 81 per cent) was larger in all neuromotor outcome categories than the number with weight (41 or 64 per cent) or length (23 or 36 per cent) below the third percentile (Table V I I I ) . FOC R E L A T E D TO O U T C O M E (FIGS. 8 AND 9) BIRTH Infants born with an FOG below the third percentile (Harvard School of Public Health) did not fare as well as infants whose birth FOC was above the third percentile. Infants with an FOG below the third percentile at birth had a slightly higher mortality rate (30 per cent vs. 20 per cent) 326 Desmond etal. The Journal o/ Pediatrics September 1967 52 -- HEAD . CIRCUMFERENCE ~ 50 ; 9 7 l h percentile 97 th percentile I- ~ . (~ 50th percentile - / 48 /~.~ 50th percentile O~ 46 ~ ( ~ 3rd percentile 3 rd percentile / 44 42 / cm. 40 r/ / 38 136 34 32 - - / t 9 Good neuromotor outcome - 9 50 I l l ) - Severe neuromotor obnormaUty (no improvement 12-18mo.) --9 9 Expired 28 26 ~ I 0 3 I I 6 AGE 9 IN I I I I I 12 15 18 21 24 MONTHS Plotted from d a t a of Harvard School of P,Jblir Health Fig. 9. Fronto-occipital head circumference in infants with congenital rubella at 18 months c o m p a r e d with standards for healthy children. D a t a equalized for sex distribution. and a higher per cent of severe neurological impairment at 18 months (62 per cent vs. 45 per cent) than the group as a whole. Twelve infants whose birth FOC was above the third percentile all survived. One-third had severe neurological impairment at 18 months. T h e median FOC of infants with no neurological involvement at 18 months (Group 1) was 45.3 am. (range of 42.5 to 50 am.). The median F o e in the most severe outcome group (Group 4) was 43 cm. (range o.f 41 to 47.5 cm.). Severe neuromotor impairment (Group 3 or 4) occurred in all infants with an FOC of 42 cm. or less. The widely open anterior [ontanel in general remained open for 9 to 12 months with rapid closure thereafter. At 18 months the majority had a small or closed anterior fontanel. The widely separated metopic suture present during the early months, closed around 9 months to form a palpable and often visible ridge, approximately 1 cm. in width. The skull was frequently brachycephalic in shape. POSTMORTEM THE CNS EXAMINATION OF Lesions of the CNS were present in 11 of the 13 patients examined at autopsy (Table X I ) . Chronic leptomeningitis occurred in 11 and was the only demonstratable lesion in 4. The infiltrate was composed of large and small mononuclear cells, lymphocytes, and plasma cells. In addition to. leptomeningitis, multiple small areas of liquefactive necrosis and glial cell proliferation were found in the paren- Volume 71 Number 3 Rubella encephalitis Fig. 10. Vasculitis: A small vessel in the pons with diffuse infiltration of the wall by round cells. (H & E stain, x200.) Fig. 11. Parenchymal necrosis: Intense focal necrosis with calcium deposits in cerebral white matter. (H & E stain, xlO0.) 32 7 328 Desmond et al. The Journal o[ Pediatrics September 1967 Table XI. CNS findings at autopsy Symptoms ] No. No lesion Chronic leptomeningitis alone Chronic leptomeningitls plus other Iesions'~ parenchymal necrosis basal ganglia (5) cerebral white matter (2) spinal cord (2) ports (1) midbrain ( 1) cerebellum ( 1) perivascular calcification in above areas subarachnoid hemorrhage Total (5) (6) ( 1) 13 *Parentheses contain specifically the number of patients with each finding. chyma in 7 patients. These lesions were distributed in the basal ganglia and Iess frequently in the midbrain, cerebral white matter, pons, and spinal cord (Figs. 10 and 11). Microscopic vasculitis and perivascular calcification occurred in 6 patients in a distribution similar to. that of inflammatory" and necrotic lesions. All but two had clinical symptomatology suggesting active CNS disease. The two without overt neurological signs had leptomeningitis at autopsy and one had multifocai areas of parenchymal necrosis in the white matter. DISCUSSION Congenital rubella is an active contagious disease with multisystem involvement and a wide spectrum of clinical expression. Although tissues are heavily infected with rubella virus, the degree of involvement varies widely at birth. Growth retardation, particularly in weight, is the most common finding at birth? After delivery, the disease process may become more severe. In this group, the first 6 months of extrauterine existence is often stormy--with the emergence of thrombocytopenia, hepatitis, pneumonitis, rhinitis, otiti% congestive failure, diarrhea, anemia, and encephalitis. (Emergency cardiac surgery was carried out in 18 infants of this series, largely between 1 and 3 months of age. Over half of the deaths occurring during the first year were among infants under 3 months of age.) Encephalitis is only one facet of a generalized disease. In over a third of this series, CNS involvement was evident from birth and continued into early infancy. In profoundly ill infants, this aspect of the disease could only be surmised by the presence of a full fontanel and hypotonia during the first 3 or 4 months of life. Overt neurological disease appeared in many only after the early emergencies had passed. Motor development was conspicuously poor during the early months. Severely ill patients progressed little beyond birth level until 4 to 6 months o,f age. When motor development began, its sequence was not orderly since head control and support of body weight lagged behind hand coordination. Socialization was also delayed, particularly in those with agitation or sensory handicaps. Between 6 and 12 months of age, the patient group began to diverge. Some improved rapidly within limits imposed by handicaps; others improved more slowly or showed a more definite type of neurological impairment. Fifteen virtually ceased to improve between 12 and 18 months. Eight of the 15 became increasingly withdrawn and autistic in behavior. Forty-four of 64 survivors remaining in the study at 18 months had one or more abnormal neurological findings. These included motor deficits, disturbances of tone and movement, seizures, and hyperactivity. Somatic growth (particularly head circumference) was impaired. All but 6 of the 64 had impaired vision, impaired hearing or poorly developed speech. Utilizing generally accepted definitions, 32 of the 64 patients may be classified as mild or severe cerebral palsy":~ and 11 as mental retardatest with associated neuromotor impairment (Figs. 12 and 13). ~Cerebral palsy--a disease of posture and movement originating in the immature brain. TM "~Mental retardation--subaverage general intellectual functioning which originates during the development period and is associated with impairment in adaptive hehavlor. 17 Volume 71 Number 3 Rubella encephalitis 329 Fig. 13 Fig. 12 Fig. 12. Hypertonic cerebral palsy in lg-month-old infant with congenital rubella syndrome. Note general growth retardation and presence of only 2 lower central incisor teeth at this age. Fig. 13. Hypotonic cerebral palsy in 18-month-old infant. Note inability of infant to extend head. The wide range of neurological disability and the varied topography of persisting motor deficits present in surviving children find a parallel in the CNS findings at autopsy, both in this series and in those previously reported. 1~ is, 19 Vasculitis, multifocal areas of parenchymal necrosis, and perivascular calcification are widely distributed in the brain and spinal cord. Leptomeningltis occurs alone or in combination with other lesions. As reported by Naeye and coworkers, is brain weight at autopsy is subnormal. T h e pathogenesis of congenital rubella is under extensive: investigation. Cells infected by the rubella virus grow more slowly than uninfected control cells and have a limited doubling capacity. 2~ Growth retardation apparent at birth is associated with a de- creased number of cells in the body organs. 18 Brain growth in the fetus with rubetla is less than that of fetuses malnourished from other causes. 18 In this series retardation of somatic growth continued after birth. At birth, retardation in weight was more common than retardation in length or small head circumference. At 18 months~ a small head circumference was more common than subnormal height or weight. A small head size at birth was often associated with early death or severe neurological impairment at 18 months of age (Figs. 8 and 9 and Table V I I I ) . Clinical evidence suggests that the insults by rubella virus to the fetal brain and neurosensory structures prenatally may in some instances be succeeded by active postnatal disease. In this series, spinal fluid protein and 330 Desmond et aI. cells were noted to increase after birth for a period of months in severely involved infants (Fig. 2 B). Three infants had an abrupt change in neurological course at 2, 3, and 7 months, respectively; 2 infants have shown progressive hearing loss after 9 months; and 1 developed glaucoma for the first time at 16 months. Persistence of rubella virus in the spinal fluid is demonstrated in this seriess (Table V). The presence of virus in the spinal fluid does not, however, correlate with neurological outcome at 18 months (Table VI). A longer clinical and laboratory experience will be required before the final significance of the continuing presence of virus in the neural fluids of the infant can be assessed. The findings of this series, as well as those reported by previous authors 1, s, 22-2~ suggest that infants with the congenital rubella syndrome frequently prove to have neuromotor residua in addition to other stigmata. Neurological abnormalities persisted in a high percentage (69 per cent) at 18 months. Although a large number, i.e. approximately half of the infants with severe impairment had bilateral cataracts, severe residua were not confined to this group (Table V I I I ) . The extent of impairment at 18 months of age is not predictable from either early (first week) clinical symptomatology or viral isolation (Table I). Severe involvement is more frequent in those with high levels of protein in the spinal fluid and in infants with seizures. The hypoglycemia and anoxia suffered during the early course of the generalized disease may also contribute significantly to neurological impairment. CONCLUSIONS Neurological aspects of the congenital rubella syndrome were studied in 100 infants. Signs referable to the CNS occurred in 81. Encephalitis was evidenced by a full anterior fontanel, increase in the concentration of spinal fluid protein, and persistence of rubella virus in the spinal fluid. Clinically, the infants were lethargic, irritable with tone disturbances, seizures, and delays in motor development and socialization. The Journal o[ Pediatrics September 1967 Of the 100 patients followed, 20 died and 64 were followed periodically to 18 months. At this age, 44 of the 64 (69 per cent) had some degree of neurological impairment. The spectrum of CNS involvement at 18 months included motor deficits (cerebral palsy,) seizures, hyperactivity, restlessness, stereotyped movements, motor delay, and lack of progress in adaptive behavior (mental retardation). Retardation of somatic growth continued to 18 months. At this age 52 of the 64 survivors (81 per cent) had a head circumference below the third percentile. Length was below the third percentile in 22 patients, and body weight in 23. At autopsy the most prominent lesions were leptomeningitis, vasculitis, and multifocal areas of parenchymal necrosis and perivascular calcification. The latter were widely disseminated throughout cerebral tissues. It is concluded that encephalitis (or encephalomyelitis) is a major manifestation of the: congenital rubella syndrome. Neurological impairment arising from transplacental infection may occur in infants in the absence of significant visual or cardiac lesions. Inasmuch as congenital rubella infection may occur without overt clinical evidence of rubella infection in the mother, the role of rubella virus as a n etiological agent in the causation of neurological disorders of prenatal origin may be larger than previously considered. We are indebted to Drs. Martha Yow, Fred M. Taylor, Stanley F. Olson, Laura Bickel, hnogene Burgdorff, R. N., Berna Dean Wise, Mr. James Pears, and Mr. Newell France for their contributions to the organization and continuance of the rubella program; to the nursing personnel, and to the many private physicians who participated. Cardiological evaluations were carried out by Drs. Dan McNamara and Colette Kohler, otologicaI examinations by Drs. Bob R. Alford and J. R. Dickey, hearing evaluations by Drs. Jack and Tina Bangs, ophthalmic examinations by Drs. Elisabeth Crawford and Milton Bonuik, electroencephalographic interpretations by i Drs. Peter Kellaway and James Crawley, de,)elopmental testing by Dr. Willie Vemiaud, Volume 71 Number 3 and statistical studies by Dr. Alan Levy and Mrs. Mary Beth Davis. Dr. William S. Fields gave valuable assistance in the preparation of the manuscript. REFERENCES 1. Gregg, N. M.: Congenital cataract following German measles in the mother, J. Ophth. Soc. Australia 3: 35, 1941. 2. Swan, C., Tostevin, A. L., Moore, B., Mayo, H., and Black, G. H. B.: Congenital defects in infants following infectious disease during pregnancy, M. J. Australia 2: 201, 1943. 3. Rudolph, A. J., Yow, M. D., Phillips, C. A., Desmond, M. M., Blattner, R. J., and Melnick, J. L.: Transplacental Rubella Infection in Newly Born Infants, J. A. M. A. 191: 843, 1965. 4. Krugman, S.: Rubella New light on an old disease, J. PEDIAT. 67" 159, 1965. 5. Kappers, J. A.: Developmental disturbance of the brain induced by german measles in an embryo of the 7th week, Acta anat. 31: 1, 1957. 6. Ycrw, M. D., Desmond, M. M., Bayatpour, M., Pineda, R., and Phillips, C. A.: Cerebrospinal fluid findings in congenital rubella, Am. Soc. for Microbiol. p. 48, 1966. 7. Monif, G. R. G., and Sever, J. L.: Chronic infection of the central nervous system with "rubella virus, Neurology 16" 111, 1966. 8. Phillips, C. A., Melnick, J. L., Yow, M. D., Bayatpour, M., and Burkhardt, M.: Persistence of virus in infants with congenital rubella and normal infants with a history of maternal rubella, J. A. M. A. 193: 1027, 1965. 9. Korones, S. B., Ainger, L. E., Monif, G. R. G., Roane, J., Sever, J. L., and Fuste, F.: Congenital rubella syndrome: Study of 22 infants, Am. J. Dis. Child. 110: 434, 1965. 10. Rorke, L. B., and Spiro, A. J.: Cerebral lesions in congenital rubella syndrome, J. PEDIAT. 70: 243, 1967. 11. Gruenwald, P.: Growth of the Human Fetus, Am. J. Obst. & Gynec. 94: 1112, 1966. 12. Lubchenco, L. O., Hansman, C., and Boyd, E.: Intrauterine growth in length and head circumference as estimated from live births at gestational ages from 26 to 42 weeks, Pediatrics 37" 403, 1966. Rubella encephalitis 331 13. Widell, S.: On the cerebrospinal fluid in normal children and in patients with acute abacterial meningoencephalitis, Acta paediat. (Suppl.) 115: 44, 1958. 14. Gyllenswgrd, A., and MalmstrSm, S.: The cerebrospinal fluid in immature infants, Acta paediat. (Suppl.) 135: 54, 1962. 15. Kite, J. H.: Flat foot and lateral rotation of legs in young children, J. Internat. College Surgeons 25: 77, 1956. 16. Bax, M. C. O.: Terminology and Classification of Cerebral Palsy, Develop Med. & Child. Neurol. 6: 295, 1964. 17. Heber, R.: A manuel on terminology and classification in mental retardation, Monograms Suppl. Am. J. Ment. Deficiency ed. 2, 1961. 18. Naeye, R. L., and Blanc, W.: Pathogenesis of congenital rubella, J. A. M. A. 194: 109, 1965. 19. Plotkin, S. A., Klaus, R. M., and Whitely, J. P.: Hypogammaglobulinemia in an infant with congenital rubella syndrome; failure of L-adamantanamine to stop virus excretion, J. PEDIAT. 69: 1085, 1966. 20. Rawls, W. E., and Melnick, J. L.: Rubella virus carrier cultures derived from congenitally infected infants, J. Exper. Med. 123: 795, 1966. 21. Paine, R. S., and Opp6, T. E.: Clinics in developmental medicine, London, Spastics Society, William Heinemann, Ltd., No. 20, 21, p. 170. 22. Lande, L.: Congenital malformations with severe damage to the central nervous system due to early fetal virus infection, J. PEDIAT. 36: 625, 1950. 23. Kirman, B. H.: Rubella as a cause of mental deficiency, Lancet p. 113, 1955. 24. Levine, E. S.: Psychoeducational study of children born deaf following maternal rubella in pregnancy, Am. J. Dis. Child. 81: 627, 1951. 25. Gesell, A., and Amatruda, C. S.: Developmental diagnosis, ed. 2, p. 156, 1965. 26. From studies of child health and development, Department of Maternal and Child Health, Harvard School of Public Health, quoted by Nelson, Waldo E., Textbook of Pediatrics, e d 8, W. B. Saunders Company, 1964, p. 49.