of Papers Presented at the 37th Annual Meeting of the Canadian
Association of Neuropathologists
In Vitro Neuroprotection
from Ionizing Radiation by Metallothionein Induction.
Fatal Vertebral Artery Rupture
Following Chiropractic Neck Manipulation.
Rods Come of Age.
Expression of Ki67 Antigen and H3 Histone Messenger RNA in
Human Fetal Brains.
is More Efficient than Lovastatin in Inducing Apoptosis of
Medulloblastoma Cell Lines In Vitro.
Caspase-cleaved Actin (Fractin)
Immunolabeling of Apoptotic Neurons in Acute Perinatal Hypoxic-ischemic
Autophagic Myopathy Induced
by Omeprazole Therapy.
Neuropathology of Bouncer
Long Evans Rat: A Novel Dysmyelinated Mutant.
Approaches to Inhibiting
Cell Proliferation in Malignant Gliomas: Histopathological
Education and Socio-economic
Status in Confirmed Alzheimer's Disease and Autopsy Controls.
Exon 5 Mutation and Malignant Glioma:
Case Report and Molecular Genetic Study.
Peritumoral Brain Edema
on CT Scan Predicts Recurrence of Meningioma.
Fatal Tumor Embolization
to Middle Cerebral Artery: An Unusual Complication of Osteogenic
Hippocampal Sclerosis in
Two Sisters with 22-Derived Marker Chromosome and Late-Onset
Dementia of Alzheimer Type.
Ganglioneuroblastoma of the
Spinal Cord: A Unique Case.
Chordoid meningiomas in adults.
Progressive Multifocal Leukoencephalopathy
Feigning Brainstem Ischemia.
in Rheumatoid Arthritis.
Loss of the NF2 Gene and Merlin
Occurs in the Tumorlet Stage of Schwannoma Development in
OF DIAGNOSTIC CASE PRESENTATIONS
Vitro Neuroprotection from Ionizing Radiation by Metallothionein
HAMMOND, L. CAI, M. LEBLANC and M.G. CHERIAN (London Health
Sciences Centre and University of Western Ontario, London,
(MT) are a family of ubiquitous cysteine-rich intracellular
proteins. They have a high affinity for metal ions and serve
to protect cells from heavy metal toxicity. There is also
evidence to show that the induction of MT is associated with
cytoprotection from a variety of oxidative stresses, including
ionizing radiation. Isoforms MT-I and MT-II are widely expressed
throughout the body. MT-IV is expressed in squamous epithelia
and MT-III is brain specific. Among the known inducers of
MT production are cadmium (Cd) and zinc (Zn). Primary serum-free
human CNS cultures were exposed to high dose ionizing radiation
with or without preincubation with Cd or Zn. The cultures
were sacrificed to examine for apoptosis, neuronal damage
and astroglial hypertrophy. Metallothionein was induced above
baseline levels by Cd and Zn. Furthermore, in those cultures
preincubated with Cd or Zn, there was morphologic and biochemical
evidence of neuroprotection in the form of reduced apoptosis,
neuronal damage and astrocytosis. These preliminary experiments
suggest that MT can be induced in CNS cells and that its induction
is cytoprotective. Likewise, it suggests a role for MT expression
in the protection of CNS cells from ionizing radiation and
other forms of oxidative stress.
Vertebral Artery Rupture Following Chiropractic Neck Manipulation.
MACAULAY (Department of Pathology, University of Saskatchewan,
neurologic sequelae following chiropractic manipulations are
seen occasionally, only rarely has death been attributed to
such procedures. This previously healthy 20 year old woman
had received approximately 20 cervical 'adjustments' over
several months. The day before admission she complained of
pain and a 'catch' in her neck, and chiropractic neck rotation
was administered on that day, and again on the following day,
after which she collapsed, convulsed for 10-15 minutes, and
did not recover consciousness. Neurological examination showed
evidence of brainstem dysfunction. Angiographically, an intraluminal
obstruction was noted in the left vertebral artery at C1-C2,
with occlusive thromboemboli in several posterior circulation
branches. Urokinase administration cleared the C1-C2 obstruction
and partly dissolved distal thromboemboli. The next day she
decompensated due to a large left cerebellar infarct. She
'coned' and died approximately 2 1/2 days after admission.
At autopsy, the left vertebral artery was lacerated adjacent
to the C1-C2 facet joint, with a small surrounding hematoma.
There was evidence of mild chronic irritation near the laceration,
but not elsewhere. The left vertebral artery was significantly
larger than the right (5mm vs 1mm in diameter respectively),
and the close proximity of the vessel to the CI-C2 facet joint
may have resulted in repeated distortion, possibly exacerbated
by passive neck manipulations. However, asymmetry of the vertebral
arteries is a common variant of normal, implying additional
unknown factors may have been operative.
Elements in Schwannomas.
ROBINSON, B. CURRY and N.B. REWCASTLE (Department of Pathology,
University of Calgary, Foothills Hospital, Calgary, AB)
pseudoglandular schwannoma is a recently described variant
in which cystic spaces are lined by pseudocolumnar or cuboidal-like
neoplastic Schwann cells exhibiting an epithelial-like appearance.
Because the incidence and significance of pseudoglandular
elements within schwannomas is unclear, we screened 215 schwannoma
cases for the presence of these elements. Sixteen cases (7.4%)
were found to contain pseudoglandular elements, and these
were subsequently examined with light microscopy, immunohistochemistry,
and electron microscopy. The pseudoglandular elements ranged
from poorly to well-organized in appearance, and were found
in schwannomas exhibiting a wide range of morphological appearances.
To one extent or another, the pseudoglandular elements were
almost always found in association with Antoni B tissue. The
Schwann cell nature of the cells comprising these elements
was apparent both immunohistochemically and ultrastructurally.
The frequency of proliferative activity within these elements
was similar to that observed throughout the remainder of the
respective schwannomas. Our observations suggest that, rather
than representing a distinct histologic schwannoma variant,
pseudoglandular elements likely arise secondarily as a degenerative
phenomenon. These elements may be found within a variety of
schwannoma variants, and do not appear to possess a unique
growth potential. Degeneration within tumor areas exhibiting
different growth patterns may contribute to the variable appearances
seen within the pseudoglandular elements.
Intranuclear Rods Come of Age.
WOULFE, D. MUNOZ and R. HAMMOND (Department of Pathology,
Division of Neuropathology, London Health Sciences Centre,
neuronal intranuclear inclusions were known to light microscopists
of the classical period and were described as early as 1894.
Subsequent electron microscopic studies confirmed the existence
of these structures and elucidated details of their ultrastructural
morphology. However, the biochemical composition of these
structures as well as their functional significance and possible
pathological relevance have remained elusive. In addition,
their localization in the human brain remains to be described.
Much of the difficulty stems from unreliable methods of demonstrating
intranuclear rods at the light microscopic level.
discovered, serendipitously, that immunostaining for the selective
neuronal cytoskeletal protein, class III beta tubulin, intensely
labels morphologically similar rod-shaped intranuclear structures
within the nuclei of neurons in the human temporal lobe. Consequently,
we exploited the expression of class III beta tubulin in these
structures to examine the topographic and intracellular distribution
of neuronal intranuclear rods in the human brain using immunohistochemistry.
Multiple sections through several regions of the human brain
were processed immunohistochemically for the demonstration
of class III beta tubulin. Intensely-immunoreactive intranuclear
rods displayed a highly selective pattern of distribution
within the human brain. Areas containing large numbers of
these structures included layers II and VI of the insular
and temporal cortices, the substantia innominata, dentate
hilum, substantia nigra pars compacta, inferior colliculus,
inferior olivary nucleus, and cerebellar dentate nucleus.
This anatomically-selective pattern of distribution of neuronal
intranuclear rods suggests region-specific functions for these
structures in the human brain and implicates them in some
of the many pathologic processes that affect the brain in
a regionally selective manner.
Cycle-related Expression of Ki67 Antigen and H3 Histone Messenger
RNA in Human Fetal Brains.
DEL BIGIO (Department of Pathology, Health Sciences Centre
and University of Manitoba, Winnipeg, MB)
information concerning cell proliferation in the developing
brain is derived from animal experiments that have utilized
pulse-labeling with thymidine analogs. Cell cycle-related
markers were studied in the frontal cerebrum of fourteen human
fetuses aged 15-28 weeks gestation. Ki67 antigen is expressed
beginning in late G1 phase and maximally in G2 and M phases.
H3 histone mRNA is expressed during S phase. Immunohistochemistry
and in situ hybridization revealed a laminar organization
of ventricular zone cells in different stages of the cell
cycle. Most S phase cells were located 60-100mm from the ventricular
lumen, supporting the concept of interkinetic nuclear migration.
The ventricular zone dissipated gradually between 20 and 26
weeks. Proliferative cell populations were also observed in
the subventricular and intermediate zones. Dorso-ventral partition
of proliferating cell populations within the ganglionic eminence
reflects differences in the developmental timing of its target
structures; the ventral portion supplies cells to the thalamus
which develops later than the striatum. [Funded by the
Health Sciences Centre and the Manitoba Health Research Council]
Inhibition is More Efficient than Lovastatin in Inducing Apoptosis
of Medulloblastoma Cell Lines In Vitro.
WANG and R.J.B. MACAULAY (Department of Pathology, University
of Saskatchewan, Saskatoon, SK)
is a malignant cerebellar tumour usually manifesting in childhood.
We have previously shown that blocking the mevalonate pathway
with lovastatin, a competitive inhibitor of 3-hydroxy-3methylglutaryl
coenzyme A (HMG-CoA) reductase, induces MB cell line apoptosis
in vitro. We also observed that lovastatin resulted in the
inhibition of p2l ras farnesylation, and suggested that blocking
protein farnesylation is important in lovastatin-induced apoptosis.
We tested this hypothesis using manumycin A, an antibiotic
which inhibits farnesyl protein transferase. We found that
blocking protein farnesylation with manumycin A is followed
by medulloblastoma cell apoptosis in a time- and dose-dependent
manner. However, cell death induced by manumycin A was more
rapid and efficient, requiring only 12 to 24 hrs of treatment,
than lovastatin-induced apoptosis, which required 36 to 96
hrs, depending on the cell line tested. In addition, unlike
lovastatin which caused cell cycle arrest in G I and HMG-CoA
upregulation, manumycin A had no effect on the cell cycle
and resulted in downregulation of HMG-CoA. In both lovastatin-
and manumycin A-treated cells, cellular cysteine protease
precursor CPP32 was activated, confirming the occurrence of
apoptosis in both phenomena. Further studies on the induction
of apoptosis in MB may lead to the development of new therapeutic
approaches. [Supported by a Grant from the Brain Tumor
Foundation of Canada]
Actin (Fractin) Immunolabeling of Apoptotic Neurons in Acute
Perinatal Hypoxic-ischemic Brain Injury.
ROSSITER1, L.L. ANDERSON1, F. YANG2 and G.M. COLE.2 (Dept.
of Pathology, Kingston General Hospital,1 ON and Sepulveda
VAMC GRECC,2 CA)
of a family of aspartate-specific cysteine proteases (caspases)
is a central feature of apoptotic cell death. Caspase activation
results in cleavage of multiple substrates, including cytoskeletal
actin microfilaments. Caspase cleavage of actin into N-terminal
~ 32 kD and C-terminal ~ 15 kD fragments has been identified
in apoptotic cell extracts. This has led to the development
of a rabbit polyclonal antibody specific for caspase-cleaved
actin, directed to the last five C-terminal amino acids of
the ~ 32 kD fragment (= fractin) (Am. J. Pathol. 1998, 152:379-389).
In this study we have examined the pattern of fractin immunolabeling
in postmortem brain tissue from 10 premature to term infants
with acute perinatal hypoxic-ischemic brain injury.
was strong fractin immunolabeling of the cytoplasm of apoptotic
neurons in vulnerable regions, including the basal pontine
nuclei, hippocampal formation and cerebral isocortex. There
was prominent fractin-labeling of the dendrites of some apoptotic
cells. Many long fractin-positive axonal segments, frequently
with a beaded appearance, were seen in the grey matter and
adjacent white matter of vulnerable areas in several cases.
findings support a role for catalytic caspase-like activity
in neuronal apoptosis, including possible activity in axons,
in perinatal hypoxic-ischemic brain injury. They also further
demonstrate the utility of fractin immunolabeling for highlighting
apoptotic neurons and their processes.
Myopathy Induced by Omeprazole Therapy.
BILBAO and G. MODDEL (St. Michael's Hospital, Toronto, ON)
inhibits gastric ATPase (the proton pump) which catalizes
the exchange of H+ and K+. Rarely muscular weakness and myalgia
have been reported as an adverse effect of this treatment.
This is the first report of a vacuolar myopathy induced by
a proton pump inhibitor.
71-year-old male presented with a two year history of increasing
difficulty in walking. Two years previously, he had started
treatment with 20 mg of omeprazole and 10 mg of cisapride
per day for gastric complaints. Examination revealed mild
generalized weakness and no neuropathic signs. CPK was 170
and EMG indicated a myopathic process. Muscle biopsy revealed
a non-necrotizing vacuolar myopathy associated with accumulation
of intrasarcoplasmic lamellar-osmiophilic bodies and exocytosis
of lysosomal debris. After cessation of treatment, the patient's
strength returned to normal within 4 months. Repeat EMG showed
no abnormality. The exact mechanism of omeprazole-induced
myopathy is not known. Cisapride does not cause muscle symptoms.
The myopathy induced by omeprazole should be added to the
list of autophagic myopathies caused by drugs such as chloroquine,
perhexiline, amiodarone, vincristine and colchicine.
of Bouncer Long Evans Rat: A Novel Dysmyelinated Mutant.
KWIECIEN, M.C. BLANCO, J.G. FOX, S.U. KIM, K.H. DELANEY, A.L.
FLETCH (McMaster University, ON, Mayo Clinic, MN, University
of British Columbia, BC)
rodents serve as useful models for studying mechanisms involved
in myelinogenesis or as recipients of oligodendroglial cells
to study remyelination. Recently, a Long Evans Shaker (LES)
rat, which is a severely dysmyelinated, long lived model with
a functional mutation in the myelin basic protein (MBP) gene,
has been described. In this presentation, results of histologic,
ultrastructural and immunocytochemical studies of the Bouncer
Long Evans (BLE) rat, a novel mutant, are shown. The BLE mutation
is transmitted in an autosomal recessive fashion and is associated
with lack of myelin in the CNS but myelin sheaths in the peripheral
nervous system appear morphologically normal. Electron microscopic
studies of rats 1-14 weeks old reveals severe dysmyelination
with scattered, thin, up to 4-5 lamellae-thick sheaths wrapped
around axons which are uncompacted and lack the major dense
line. Oligodendrocytes (OL) degenerate in a progressive fashion
with accumulation of a membranous material, presumably of
a lipid nature, in the perikaryon. OL necrosis is evident
and at 8-14 weeks there are numerous immature glial cells
of OL type in the optic nerve and spinal cord. Astrogliosis
is severe and diffuse, microgliosis is diffuse but not intense.
Specific antibody labelling of paraffin embedded sections
of the CNS revealed no detectable MBP and proteolipid protein.
The BLE rat survives beyond 19 weeks and may prove a useful
model for studying mechanisms of myelinogenesis and glial
proliferation in the adult CNS. While definite molecular experiments
elucidating the nature of the mutation are pending, the BLE
rat is presumed to be affected by a functional mutation in
the MBP gene. [Funded by the Myelin Project of Canada].
to Inhibiting Cell Proliferation in Malignant Gliomas: Histopathological
REWCASTLE, M. LAFLEUR, L.L.GROFT, M.E.WILCOX, H.MUZIK, S.Q.
SHI, D.EDWARDS, P. LEE and P. FORSYTH (University of Calgary,
malignant gliomas are characterized by profuse vascular proliferation
and cell invasion of adjacent tissues. It is hypothesized
that imbalances between tissue metalloproteinases and the
tissue inhibitors of metalloproteinases (TIMP's) may allow
for such tumor growth. In-situ hybridization localized TIMP's
to glioma cells but in addition TIMP's 1 & 4 localized
to proliferating blood vessels suggesting a role in angiogenesis
regulation. In contrast to gelatinase A, gelatinase B was
highly expressed in vessels at the growing tumor margin again
suggesting a role in angiogenesis. Using a subcutaneously
implanted human malignant glioma cell line (U87) in SCID-NOD
mice, the synthetic matrix metalloproteinase inhibitor AG3340
produced a marked impediment to tumor cell proliferation compared
to controls. Viral therapy as a means of interfering with
cell proliferation has been applied to gliomas. Reo virus
selectively infects Ras-activated cells that includes glioma
cells but not normal cells. Using the same experimental mouse
model with intra-tumor and remote administration, Reo virus
produced a striking inhibition of tumor growth compared to
controls (p=0.0001). Morphological findings supporting these
observations will be presented. (Funded in part by the Alberta
BILBAO and S. COHEN (St. Michael's Hospital, Toronto, ON)
is found in about 5% of patients with cryptogenic peripheral
neuropathy. In 771 consecutive cases of peripheral nerve biopsy
collected over a 26 year period, we identified 6 cases of
polyneuropathy associated with non-amyloidgenic paraproteinemia.
Four of the patients had IgM monoclonal gammopathy. Non-specific
histologic changes included patchy and perivascular mononuclear
cell infiltrates, axonal degeneration, segmental demyelination,
and remyelination with onion bulbs. Specific changes were
congo-red negative amorphous deposits (one case) and widely
spaced myelin (3 cases). Immunohistochemistry demonstrated
the preeminence of immunofluorescence (frozen tissue) and
immunogold (on etched plastic sections) over immunoperoxidase
(on paraffin section) for the identification of deposits of
clonal immunoglobulin in peripheral nerve.
and Socio-economic Status in Confirmed Alzheimer's Disease
and Autopsy Controls.
MUNOZ, G.R. GANAPATHY, M. ELIASZIW and V. HACHINSKI (The University
of Western Ontario, London, ON)
number of epidemiological studies in several countries, including
Canada, have reported that low educational attainment is a
risk factor for Alzheimer's disease (AD). However, diagnosis
was obtained by clinical observation only, without pathological
confirmation. We have previously reported that educational
attainment did not influence the rate of cognitive decline
in patients with pathologically confirmed AD. Moreover, less
educated patients were older at onset, contrary to the predictions
of the "brain reserve" hypothesis on the mechanism of action
of education. In the present study we have obtained through
telephone interviews with relatives the educational attainment
and socio-economic status of 115 patients with Alzheimer's
disease enrolled in the University of Western Ontario Dementia
Study and 181 non-demented individuals over the age of 65
autopsied at the University Hospital of London, Ontario. All
results were adjusted for sex, age at death, and year of birth.
There were no statistically significant differences in education
or socio-economic level between the two groups. Similar results
were obtained when analysis was repeated for the subgroup
of patients in the work force.
5 Mutation and Malignant Glioma: Case Report and Molecular
TAYLOR,7 J. PERRY,4,7 M.C. ZLATESCU,1,8 A.O. STEMMER-RACHAMIMOV,2,6
L.C. ANG,3,7 Y. INO,2,6 M. SCHWARTZ,7 L.E. BECKER,5 D.N. LOUIS2,6
and J. G. CAIRNCROSS1,8 (London Regional Cancer Centre1, Massachusetts
General Hospital,2 Sunnybrook Health Sciences Centre,3 Sunnybrook
Regional Cancer Centre,4 Toronto Hospital for Sick Children,5
and Universities of Harvard,6 Toronto,7 and Western Ontario,8)
with Turcot syndrome (TS) are predisposed to colon tumours
and primary brain tumours, typically glioblastomas or medulloblastomas.
We describe a TS patient with a known germline mutation of
exon 5 of the hPMS2 mismatch repair gene who developed two
metachronous glioblastomas, both having distinct oligodendroglial
features. Molecular genetic analysis showed that the patient's
second tumour had allelic loss of chromosome 19q but lacked
allelic loss of chromosome 1p. The tumour also had prominent
microsatellite instability, consistent with a germline mismatch
repair defect. Because this patient had an unusual underlying
condition and his tumour had a unique histological appearance
for TS, we hypothesized that this genetic defect may predispose
to malignant gliomas with oligodendroglial features. We therefore
evaluated whether sporadic glioblastomas and oligodendrogliomas
undergo mutations of this region of the hPMS2 gene. Single
strand conformation polymorphism analysis of hPMS2 exon 5,
however, failed to reveal mutations in 20 sporadic glioblastomas
and 16 sporadic oligodendroglial gliomas. Thus, while it is
possible that germline hPMS2 exon 5 mutation may predispose
to glioblastomas with an oligodendroglial component, the same
genetic defect is not commonly involved in sporadic oligodendrogliomas
Brain Edema on CT Scan Predicts Recurrence of Meningioma.
MANTLE, B. LACH, M. DELGADO, S. BAEESA and G. BELANGER (Ottawa
Civic Hospital, Ottawa, ON)
10% of meningiomas recur after gross total resection, presumably
due to residual tumor cells in the meninges or brain parenchyma.
Our objective was to determine whether peritumoral edema on
CT could be correlated with pathologic brain infiltration
and clinical recurrence.
132 cases of intracranial meningioma resected at our
hospital from 1980-92 were assessed and followed to the present
day. Blinded grading of edema on initial CT scan and pathologic
determination of brain infiltration were done by a neuroradiologist
and a neuropathologist respectively. Linear regression with
Spearman rank correlation analysis was used to compare the
degree of edema graded in subjective average radial cm with
brain infiltration and recurrence.
The recurrence rate was 22% overall and 11% after
gross total resection. Mean time to recurrence was 6y (SD
± 4), mean follow up was 11y (SD ± 4 yrs). The quantity
of peritumoral edema correlated linearly with the chance of
brain infiltration (rS = 0.95, p = 0.002), and recurrence
(rS = 0.98, p < 0.0001).
The strong correlation between degree of edema and
chance of brain infiltration suggests that infiltration causes
peritumoral edema. Edema also predicted recurrence according
to a 15% rule: the chance of recurrence (assuming complete
resection) increases by 15% for every cm of peritumoral edema.
Edema on CT could provide a guide to surgeons with respect
to the need for a peritumoral resection margin.
Tumor Embolization to Middle Cerebral Artery: An Unusual Complication
of Osteogenic Sarcoma.
RAO, F. SCHNEIDER, C. AKMAN, V. ANDERSON and S. AHMED (Kings
County Hospital Center and State University of New York Health
Science Center at Brooklyn, NY)
osteogenic sarcoma is a rare tumor either as a primary or
as a metastasis. Tumor emboli from an osteogenic sarcoma occluding
the middle cerebral artery resulting in infarction of the
distribution territory has not been reported. We present such
a case of a 17 year old girl who was diagnosed having osteogenic
sarcoma of right fibula for which she underwent amputation
and chemotherapy. She developed pulmonary metastases which
were resected. She appeared to be in remission with a normal
chest CT in early 1998. Her final admission to the hospital
was with generalized tonic clonic seizures and a left focal
tonic seizure. Twelve hours after admission her neurological
examination revealed dilated and fixed pupils, non reactive
to light. Her extremities were flaccid with absent deep tendon
reflexes and plantar response. CT scan was consistent with
hypoxic encephalopathy. Autopsy revealed extensive metastases
in the lungs and in the inferior vena cava. The brain showed
evidence of permanent global ischemia and non perfusion. The
right middle cerebral artery revealed occlusion by tumor embolus
and it's distribution territory showed evidence of acute infarction
by presence of polymorphonuclear margination and migration
into the infarcted tissue. Sections from other areas of the
brain showed acutely hypoxic neurons only. Pituitary gland
showed acute infarction.
Sclerosis in Two Sisters with 22-Derived Marker Chromosome
and Late-Onset Dementia of Alzheimer Type.
M.E.PERCY,2 P.ST.GEORGE-HYSLOP2 and D.A.RAMSAY3 (University
of Calgary,1 University of Toronto,2 and University of Western
and colleagues reported a family in which two sisters with
probable dementia of Alzheimer type were found to have an
unusual 22-derived marker chromosome, containing an expanded
region coding for ribosomal RNA (Am J Med Genet 1991; 39:307-13
and 1993; 47:14-19). We here report the neuropathologic features
and further genetic information in these two sisters. In III-3
and III-4 of the 1991 report, the age at death was 88 and
83 years, duration of dementia about 17 and at least 20 years,
and brain weights 1061 and 954 grams, respectively. Each case
had severe frontal, parietal, and temporal atrophy. Microscopically,
both cases had hippocampal sclerosis, with extreme cell loss
in CA1 and subiculum. Neurofibrillary tangles were found in
neocortex of both cases, rarely in III-3 and more frequently
in III-4. Cortical plaques were common in both. Severe neuronal
loss and gliosis in cortex, and neuronal loss in substantia
nigra, were found in both cases. Both sisters were of ApoE
3/4 genotype, and neither carried any of the known mutations
for APP, presenilin 1, or presenilin 2.
sclerosis is recognized as a common pathologic substrate of
dementia in the elderly, with variably associated Alzheimer
pathology. To our knowledge familial cases are uncommon, and
the present subjects represent the first with extensive genetic
of the Spinal Cord: A Unique Case.
H. GEORGE and R. GRIEBEL (Royal University Hospital, Saskatoon,
Ganglioneuroblastomas (GN) are well defined neoplasms
of the peripheral sympathetic nervous system (PNS). GNs of
the central nervous system (CNS) are even more uncommon, and
less well characterized. They have been described in the brain,
and have been variably categorized as forms of neuroblastoma
or ganglion cell tumor; behaviour is unclear. GNs are almost
unknown in the spinal cord, however. By contrast, the fully
differentiated ganglioglioma (GG) is a recognized entity in
the spinal cord. Spinal GGs develop most commonly in children,
usually in cervico-thoracic segments, and sometimes form dramatic
masses extending along most or all of the cord. The behaviour
of GGs is generally benign, and treatment is surgical resection,
facilitated by a usual tissue plane.
In this abstract, we present a unique case of a GN
of the spinal cord. It presented subacutely in a 3 year old
male child with torticollis and mild gait disturbance. It
formed an intramedullary mass with an extraordinary length
from C3 to T8. Subtotal surgical resection (90%) was achieved
with no residual neurological deficit. By analogy to the GN
of the PNS, the tumor is favorable histology, intermixed subtype.
Although follow-up is presently too short to determine prognosis,
the clinical and radiological features of this tumor suggest
a close relationship to the benign GG of the spinal cord,
rather than to high grade neuroblastoma.
meningiomas in adults.
SHANNON, C. BERGERON and L.C. ANG (Division of Neuropathology,
Sunnybrook Health Science Center and The Toronto Hospital,
Western Division, Department of Laboratory Medicine and Pathobiology,
University of Toronto, ON)
meningiomas are unusual tumors which, in pediatric patients,
are strongly associated with iron-resistant anemia and occasionally
hypergammaglobulinemia. These systemic manifestations are
thought to be related to the reactive chronic inflammatory
response within the tumor. Few studies of chordoid meningiomas
in adults are available. This report describes five chordoid
meningiomas in patients ranging in age from 29 to 53 years.
Three patients were female, two were male; three tumors involved
the cerebral convexities, one was parafalcine and one was
in the pineal region. All tumors were composed primarily of
epithelioid cells in an abundant mucoid matrix. Only one tumor
contained a heavy lymphoplasmacytic inflammatory reaction.
Two contained only sparse lymphoid aggregates and two lacked
any significant inflammation. One patient suffered anemia;
she had a mild normochromic anemia (Hb=112g/L) and her tumor
lacked an inflammatory infiltrate. Two tumors contained small
areas with unusual patterns of differentiation. One contained
small aggregates of cells surrounding PAS (+) material; these
aggregates were reactive with immunohistochemical stains for
cytokeratin and CEA. Another tumor had distinctly microcystic
areas and invaded the underlying brain. The dense inflammatory
infiltrate and accompanying anemia in chordoid meningiomas
is less common among adults than children. The presence of
microcystic and secretory differentiation in this series is
unusual and may reflect phenotypic plasticity in these tumors.
Multifocal Leukoencephalopathy Feigning Brainstem Ischemia.
S. JOHNSON (University of Alberta, Edmonton, AB)
the protean manifestations of progressive multifocal leukoencephalopathy
(PML), none can be more misleading in presentation than primary
involvement of the brainstem and cerebellum. Described in
this report is a rare case in an 80 year old woman who had
a 40 year history of rheumatoid arthritis controlled by immunosuppressive
therapy. Diplopia, vertigo and frequent falling heralded her
neurologic disorder, which was later compounded by dysphagia
and episodic visual loss in the left eye. Examination disclosed
palsies of the right sixth, right seventh, and left eleventh
cranial nerves accompanied by ocular bobbing, hypertonia of
the left limbs, and unsteadiness. No abnormalities were found
in studies of the CSF or CT imaging. An MRI scan, however,
showed an increased T2 signal in the brainstem interpreted
as ischemia. Death, approximately 12 weeks after presentation,
was preceded by precipitous neurologic decline. Patchy demyelination
with features characteristic of PML was strewn the length
of the brainstem, the tegmentum bearing the brunt. In situ
hybridization confirmed the presence of DNA sequences of the
JC strain of Papova virus in Cowdry A intranuclear inclusions
found within several oligodendrocytes in the most recent lesions
in the rostral brainstem and cerebellar hemispheres. A few
tiny foci of demyelination were noted in the cerebrum. Selection
of the brainstem in this patient as the primary site of infection
is enigmatic, but attests to the need to consider PML in the
differential diagnosis of brainstem syndromes.
Ophthalmoplegia in Rheumatoid Arthritis.
RAO, J. SCHNELLER, S. NAJENDRA and M. WRZOLEK (Kings County
Hospital Center and State University of New York Health Science
Center, Brooklyn, NY)
arthritis (RA) is a chronic multisystemic disease with deforming
arthritis as the outstanding feature. Atlanto-axial subluxation
resulting in cervical myelopathy is a common neurological
complication of RA as is entrapment or angiopathic neuropathy.
Rheumatoid vasculitis and rheumatoid granulomas in the central
nervous system are uncommon complications of RA. Rheumatoid
granulomas involve craniospinal dura and leptomeninges and
rarely choroid plexus or cerebral parenchyma. We report an
autopsy case of an unusual neurological complication of RA
manifesting as painful ophthalmoplegia due to involvement
of cavernous sinus structures. This 65-year old male with
history of RA presented with diplopia, ptosis, proptosis and
severe pain in the left eye. Patient expired of extensive
bilateral bronchopneumonia. Autopsy revealed rheumatoid vasculitis
in the leptomeninges and many classical rheumatoid granulomas
in the dura and leptomeninges. Sections of left cavernous
sinus showed rheumatoid granulomas involving the wall of the
sinus, perineurium of the cranial nerves and adventitia of
internal carotid artery. Trigeminal nerve was involved by
endoneurial vasculitis, inflammation, rheumatoid granulomas
and changes secondary to compression by the granulomas. Previously
a single case of painful ophthalmoplegia in RA is reported
without documentation of pathological changes in the cavernous
sinus (Dornan. JNNP 1979).
of the NF2 Gene and Merlin Occurs in the Tumorlet Stage of
Schwannoma Development in Neurofibromatosis 2.
STEMMER-RACHAMIMOV, Y. INO, Z.Y. LIM, L.B. JACOY, M. MACCOLLIN,
J.F. GUSELLA, V. RAMESH and D.N. LOUIS (Molecular Neuro-Oncology
Laboratory and Molecular Neurogenetics Unit, Massachusetts
General Hospital and Harvard Medical School, Boston, MA, USA).
of the NF2 (neurofibromatosis 2) gene-encoded protein merlin
is a universal finding in sporadic and NF2-associated schwannomas.
Certain NF2 patients may develop numerous minute Schwann cell
tumorlets of the spinal nerve roots in addition to larger,
frank schwannomas and thereby provide an opportunity to investigate
the timing of NF2/merlin loss in Schwann cell tumorigenesis.
We studied an NF2 patient with a germline NF2 gene frameshift
mutation who had many Schwann cell tumorlets and schwannomas.
Loss of heterozygosity studies of DNA from microdissected
specimens showed allelic loss of the NF2 region of chromosome
22q in tumorlets as well as schwannomas. Immunohistochemistry
further demonstrated loss of merlin expression in tumorlets
as well as schwannomas, with intact expression in adjacent
nerve. Thus, loss of both NF2 alleles and merlin occur early
in Schwann cell tumorigenesis, before the tumorlet stage.
The study of tumorlets and schwannomas in such patients may
also provide an opportunity to elucidate mechanisms responsible
for the subsequent growth of Schwann cell lesions into symptomatic
tumors. [Supported by NIB grants NS24279 and CA51410 and
by a grant from the U.S. Army.]
of Diagnostic Case Presentations