Journal of Neurology, Neurosurgery, and Psychiatry, 1979, 42, 357-362

Chronic polioencephalitis with cerebral atrophy ininfantile X-linked hypogammaglobulinaemiaBOLESLAW H. LIWNICZ AND VINCENT A. MARINKOVICH

From the Department of Pathology (Neuropathology), Stanford University School of Medicine,Stanford, California, USA

SUMMARY The development of a chronic polioencephalitis is reported in a patient withinfantile X-linked hypogammaglobulinaemia (IXH, Bruton type agammaglobulinaemia). Inearly childhood, the patient had multiple episodes of purulent inflammation involving themeninges and respiratory tract. He was given continuous administration of gammaglobulin andintermittent treatment with antibiotics, and survived for 21 years. The neuropathological lesion,which revealed severe cerebral atrophy, is described.

Children with infantile X-linked hypogamma-globulinaemia (IXH) have a propensity to developbacterial infections which in the central nervoussystem take the form of purulent meningitis. Onthe other hand, encephalitis of proven or presumedviral aetiology is rare (White et al., 1972; Linne-mann et al., 1973; Scaravilli and Coutinho, 1973;Wilfert et al., 1977). In this report we describe aclinically, immunologically, and pathologicallywell-documented case of a chronic active polio-encephalitis of four years' duration in a 21 yearold patient with IXH.

Case report

The first four years of life were uneventful, exceptfor lack of response to smallpox vaccination andsevere chickenpox. He was fully immunised withdiphtheria-pertussis-tetanus toxoids and oral poliovirus vaccination. Tine tests for tuberculosis wererepeatedly negative. There was no history of in-fection or vaccination with measles virus. In 1955,at the age of 5 years, 5 months, the patient de-veloped Hemophilus influenzae meningitis withempyema, for which three subdural taps were per-formed. One year later he had a pneumococcalmeningitis complicated by severe seizures, requir-ing general anaesthesia. Over the next two yearsthe patient suffered six or seven episodes of pyo-genic pneumonia. Serum studies performed at that

Address for reprint requests: Dr Boleslaw H. Liwnicz, Department ofPathology, University of Cincinnati College of Medicine, 231 BethesdaAvenue, Room 1101, Cincinnati, Ohio 45267, USA.Accepted 16 October 1978

time showed gammaglobulin deficiency, and thepatient was started on intramuscular gamma-globulin administration. Over the next seven years,until 1966, there were no major episodes of pneu-monia, but a progressive bronchiectasis requiredsurgical removal of the middle and lo'wer lobes ofthe right lung and the lower lobe of the left lung.Laboratory data obtained before operation ex-cluded cystic fibrosis. A year later bilateral maxil-lary drainage was performed for purulent sinusitis.

Multiple serological studies performed between1967 and 1971 revealed IgG deficiency, with levelsranging from 13.2-34.5 g/l, averaging 15 g/l, andundetectable levels of IgA and IgM. The phyto-haemagglutinin lymphocytic stimulation testwas repeatedly within normal limits. Peripheralblood white cell counts were within normal limits,with lymphocytes averaging 30%. The bone mar-row aspirate showed a lack of plasma cells.The family history was noncontributory. The

results of laboratory tests and the history of puru-lent infections were diagnostic of infantile X-linked hypogammaglobulinaemia (IXH, Brutontype agammaglobulinaemia).The two episodes of meningitis in 1955 and

1956 left the patient with some degree of mentalimpairment and hearing loss. In 1967 left sidedchronic subdural haematoma was treated by crani-otomy, resulting in transient improvement. Thesubdural haematoma recurred, and a secondcraniotomy was performed. Neurological exam-ination at the end of 1967 showed a slight inten-tional tremor, more accentuated on the right,tremor of the tongue, and an' unsteady gait.

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Neurological studies were otherwise within normallimits. Pneumoencephalography showed cerebralatrophy and adhesion to the site of craniotomy.Lumbar spinal tap revealed clear fluid with threeneutrophils, and four lymphocytes per mm3, pro-tein 0.2 g/l, and glucose 3.3 mmol/l. An EEGshowed bitemporal central slowing with dominantactivity at approximately 8 Hz.Two years later, in 1968, the patient showed

postural and intentional tremor with dysmetria.There was some muscular rigidity, and the deeptendon reflexes were hyperactive. Over the pre-vious two years the patient's mental status haddeteriorated severely, and his IQ had diminishedfrom 70 to 50.Over the next two years (1969-1971), his mental

status deteriorated further, leading to severe de-mentia. Abnormalities appeared also in cerebellarfunctions, with bilateral dysdiadochokinesis, awide based gait, and a positive Romberg sign. Thebasal ganglia changes were manifested by a mask-like facies and a right unilateral pill-rolling tremor.There was generalised decrease of muscle strengthand a bilateral increase of deep tendon reflexes.The cranial nerve examination remained withinnormal limits. Pneumoencephalography showedincreasing hydrocephalus, and the cerebral angio-gram a left subdural haematoma.Within a few months further deterioration oc-

curred, resulting in loss of normal associativemotor activities, loss of spontaneous horizontalgaze, and limitation of vertical gaze. Later thatyear the patient aspirated gastric content, de-veloped pneumonia, and died at the end of August1971, at the age of 21 years.

Necropsy findings

CENTRAL NERVOUS SYSTEMThe brain was markedly atrophic (Figs. 1,2),weighing 890 g, and surrounded by an enlargedsubdural space containing multiple membranesand straw-coloured clear fluid. The gyri werenarrowed, and the cortical ribbon was thinned,measuring 2-3 mm. The entire ventricular systemwas somewhat enlarged, with no gross evidence ofobstruction.

Microscopic examination showed a moderateinflammatory infiltration of the meninges, com-posed mainly of lymphocytes with some macro-phages containing haemosiderin and occasionalneutrophils. The meningeal veins showed a mod-erate degree of lymphocytic infiltration. All areasof the central neuraxis showed cellular featurescharacteristic of an active chronic polioencephalitis(Figs. 3-5). The distribution of the inflammatory

Fig. 1 Brain with predominantly frontal cerebralatrophy, weighing 890 g.*.t,.........Fig. 2 Coronal section of brain showing thinnedcortical ribbon and moderate ventricular dilatation.

...............

...:...Fi. 3.Lowpowe ve of cerbra co x s~~~~~~~~~~~~~~~. .. .. ..g

'..............*; ,~~~~~~~~~~~~~~~..chyma is shown in the Table. Thecerebrl..Fig.~~~~~~~~~~.opowerofcrba.ore hwn

lesions were confined mainly to the three super-ficial layers. The cellular lesions in the spinal cord

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Chronic polioencephalitis with cerebral atrophy inIXH3

Fig. 5 Microg.al nodule presumably neuronophagiain pyramidal layer of hippocam pal formation.(Haematoxvlin-eosin, original miagnification X 192).

Fig. 4 Perivascular lymphocytic cuffing and microglialnodules in cerebral cortex. (Haematoxvlin-eo sin.original magnification X75).

involved the dorsal horns and dorsal columns ofthe thoracic segments. No intranuclear or intra-cytoplasmic inclusions were seen in the centralnervous system.

LYMPHOID TISSUE

There was a generalised sparseness of the lymphoidtissue with a few small lymph nodes, lymphoid-depleted tonsils, spleen, appendix, and only asingle Peyer's patch within the examined sectionsof the small intestine (Fig. 6). The lymphoid tissuehad a prominent reticular network, with a lack ofgerminal centres (Figs. 7,8). No plasma cellswere seen. The thymus revealed well-developedepithelial structures with prominent Hassall'scorpuscles (Fig. 9). The bone marrow was hyper-cellular, with a marked increase of the myeloiderythroid ratio.

Table Manifestation of chlronic active polioencephalitis: topographic and quantitative evaluation

Site Neuronial loss Neuronophagia Microglia nodules Vascular cuffing Gliosis

Cerebrum Cortex + + + + + + + + +White matter 0 0 + + +Hippocampat formation + + + + + + + 0Striatum + + + + + + +Thalamus + + + + + + +Hypothalamus 0 0 0/ + 0/ + 0

Cerebellum Cortex (Purkinje cells) + + + + + + +White matter 0 0 + + ++Dentate nucleus + + + + + + + +

Mesencephalon Cranial nerves nuclei + + + + + + +Substantia nigra + + + ++ + + +Other neuronal structures 0 0 + + +

Pons Cranial nerves nuclei + + + + + + +Locus coeruleus 0 0 0 0 0Pontine nuclei + + + + + + +

Medulla Cranial nerves nuclei 0 0 0/ + + +Inferiorolives + + + + + + + +

Spinal cord Grey matter + + + + +White matter 0 0 + + +

F

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Fig. 6 Absence of lymphoid tissue in wall ofappendix. (Haematoxylin-eosin, original magnificationX75).

Fig. 7 A bsence of germinal centres in a lymph node.(Haematoxylin-eo.sin, original magnification X 75).

Fig. 8 Lymph node shiowing a sparsity of lymphocytesand prominent sinu5oids. (Haematoxylin-eo sin, originalmnagnification X 300).

Fig. 9 Thymus with well-developed Hassall'scorpuscles. (Haematoxylin-eosin, original magnificationX 75).

Discussion

We report a patient with infantile X-linked hypo-gammaglobulinaemia, well documented by immun-ological studies, who apparently responded well togammaglobulin adminstration and survived for 21years. During the last four to five years of life thepatient experienced a progressive psychoneuro-logical deterioration. The postmortem examinationshowed evidence of a chronic active polioencepha-litis with some white matter and meningeal involve-ment. The inflammatory lesions consisted ofmicroglial nodules and perivascular lymphocyticcuffing, most prominent in grey matter structures,and minimal in the white matter. There was alsoa neuronal loss of varying degree in different ana-tomical structures.

While several cases of encephalitis complicatingcellular immunodeficiency are on record, only afew verified cases of IXH with encephalitis havebeen reported so far. Extensive morphologicaldata can be found in the cases reported by Whiteet al. (1972) and Scaravilli and Coutinho (1973).In both, children with IXH developed chronicencephalitis. White et al. (1972) described a 10year old boy with a two and a half year historyof neurological symptoms. In Scaravilli andCoutinho's case (1973) a 6 year old boy had a fouryear neurological history. In both cases there wasbrain atrophy and neuronal loss within the cere-bral cortex and the Purkinje cell layer of cere-bellum. In the case described by White et al.(1972), as in ours, there was involvement of thebasal ganglia, which was not present in Scaravilliand Coutinho's case. White et al. (1972) wereimpressed by the degree of cerebral and cerebellarwhite matter gliosis, suggesting a resemblance to

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Chronic polioencephalitis with cerebral atrophy in IXH

subacute sclerosing panencephalitis. In the case ofScaravilli and Coutinho (1973) and in our case thegliosis was not so extensive. The inflammatory re-action in both reported cases was composed ofmicroglial nodules and lymphocytic perivascularinfiltrates. Structures resembling type A intra-nuclear inclusion bodies were found in the Purkinjecells in the case of Scaravilli and Coutinho (1973).Although no viral studies were performed, theauthors postulated a viral aetiology of the encepha-litis. As a humoral immunodeficiency IXH shouldnot ordinarily predispose to viral infections. Theauthors imply that the viral infection was enhancedby administration of hydrocortisone which isknown to cause cellular immunosuppression.

Viral encephalitis confirmed by virologicalstudies is reported in two cases by Linnemann etal. (1973). In both cases there was an infection bytwo concomitant viruses: measles with herpessimplex, and echovirus with herpes simplex. Inboth cases the encephalitis had a short, fatalcourse, and postmortem examination in the caseof measles-herpes simplex infection revealed acuteencephalitis with type A intranuclear inclusionbodies. The authors suggest that in these cases cel-lular immunity was depressed by one virus, thusenhancing the severity of infection by the secondvirus. This is in agreement with existing evidencethat measles virus suppresses cellular immunity(Burnet, 1968; Fireman et al., 1969; Saunders etal., 1969), and that echovirus is known to inhibitlymphocytic transformation (Willems et al., 1969).A different explanation is offered by Wilfert et al.(1977) in their report of five cases of echovirus in-fection in agammaglobulinaemia with absence ofsurface immunoglobulin bearing B lymphocytes.The authors postulate that intact B cell function isessential for the eradication of echovirus infectionin the central nervous system. Among the five re-ported cases only one had a postmortem exam-ination, and that 24 year old man with a two yearhistory of neurological symptoms showed a pan-encephalitis with severe white matter inflammation,and only a moderate degree of gliosis. Spinal cordinvolvement was not documented in any of theabove discussed cases. In our case, however, therewas some degree of poliomyelitis and posteriorcolumn involvement, seen mainly in the thoracicsegments.

In the case reported by Chang et al. (1966) of a7 year old boy with IXH, the patient had paralyticpoliomyelitis which developed seven weeks afteradministration of type 1 poliomyelitis virus vaccine.The postmortem examination and virologicalstudies confirmed the diagnosis. It is of interestthat the vaccinated virus was still demonstrated in

the pharynx seven weeks after it was fed, whilein normal individuals the virus cannot be detectedin this area after 10 days.On the basis of these few and unevenly docu-

mented cases it is difficult to establish the patho-genesis and aetiology of IXH-related encephalitis.In most of the reviewed cases a polioencephalitiswith a varied, sometimes severe, degree of whitematter involvement is reported. There can also bespinal cord involvement, as a separate occurrenceor along with encephalitis. The aetiology is mostcommonly thought to be a viral infection, but theevidence is not always satisfactory. The inflam-matory lesions are always composed of perivascularlymphocytic cuffing, microglial nodules, and avariable degree of diffuse lymphocytic infiltration.Intranuclear inclusion bodies are inconstant. In ourcase there was extensive brain atrophy and hydro-cephalus, a common feature of chronic encepha-litis (Jellinger and Seitelberger, 1967; Forno, 1970;Ogawa et al., 1973). It is impossible, however, toevaluate to what extent the hydrocephalus was asequel to the early childhood meningitis.

In conclusion, the reported case is an exampleof IXH long survival punctuated by repeatedbacterial infections, both meningeal and pul-monary, and culminating in a chronic active polio-encephalitis of unknown causation, displayingmorphological features similar to those reportedin previous cases with viral aetiology.

Supported by Graduate Neuropathology TrainingGrant 5 TOI NS5500-11 from the National Insti-tute of Neurological and Communicative Diseasesand Stroke, US Public Health Service. Dr L. S.Fomo, Dr L. J. Rubinstein, and Professor H.Urich gave advice and criticism on the manuscript,Ms M. A. Lawrence and Mr R. A. McGowan gavetechnical help, and Mr P. Horne gave photographicassistance.

References

Burnet, F. M. (1968). Measles as an index of immun-ological function. Lancet, 2, 610-613.

Chang, T. W., Weinstein, L., and MacMahon, H. E.(1966). Paralytic poliomyelitis in a child withhypogammaglobulinemia: probable implication oftype 1 vaccine strain. Pediatrics, 37, 630-636.

Fireman, P., Friday, G., and Kumate, J. (1969).Effects of measles vaccine on immunologic respon-siveness. Pediatrics, 43, 264-272.

Forno, L. S. (1970). Chronic atypical encephalitis. Areport of 4 cases. In VIth International Congress ofNeuropathology, pp. 1156-1157. Masson: Paris.

Jellinger, K., and Seitelberger, F. (1967). Pseudo-systematische Lesionen bein "atypischen" encepha-litiden. A cta Neuropathologica, 8, 185-209.

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