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Central neurogenic hyperventilation in a conscious patient with primary cerebral lymphoma.

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sively inherited cerebellar ataxia [9}, in adults with
dominantly inherited olivocerebellar atrophy (Holmes
type) C4, 111, and in patients with alcoholic or nutritional cerebellar degeneration 13. This similar localization of atrophy in infantile and adult-onset cerebellar
ataxia syndromes suggests that the anterior cerebellar
vermis is unusually susceptible to various degenerative
processes. Other areas of the cerebellum are involved
at the microscopic level, however "j, 7f. Thus, we
cannot assume that all clinical findings are due to the
atrophy of the anterior vermis.
The cerebellar atrophy in our patients may be a
manifestation of an early-onset degenerative process or
may be related to a localized hypoplasia. Microscopic
study of the cerebellum in the few reported individuals
with early-onset cerebellar ataxia { S , 73 revealed predominantly granule cell loss, some Purkinje cell loss,
reactive gliosis, and preservation of pericellular basket
fibers, all suggestive of a degenerative process. Patients
reported with true hypoplasia of the cerebellar vermis
have distinctly different clinical syndromes. With
Joubert's syndrome [ 3 , 61 agenesis of the cerebellar
vermis is associated with episodic hyperpnea, ataxia,
severe mental retardation, and poorly defined eye
movement abnormalities. A subgroup of patients with
Leber's retinal degeneration have hypoplasia of the
cerebellar vermis and also visual loss El2).
In one of our family members, Patient 4, a normal
MRI scan was obtained; he had a forme fruste of the
syndrome seen in his mother and sisters. Thus, despite
the absence of objective evidence on MRI of atrophy
of the cerebellar vermis, it is likely that this patient has
cellular damage that is the same in distribution, although not in extent, as that in the other family members.
Dr Furman is supported by Grant NS 00764, and Dr Baloh by
Grants NS 09823 and EY 04556, from the National Institutes of
Health.
References
1. Adarns RD: Nutritional cerebellar degeneration. In Vinken PJ,
Bruyn GW (eds): Metabdic and Deficiency Diseases of the
Nervous System, Part I1 (Vol28, Handbook of Clinical Neurology). New York, ElsevidNorth Holland, 1976, pp 271-283
2. Batten FE: Ataxia in childhood. Brain 28:484-505. 1905
3. Boltshauser E, Isler W: Joubert syndrome: episodic hyperpnea,
abnormal eye movemenrs, retardation and ataxia, associated
with dysplasia of the cerebellar vermis. Neuropaediatrie 8:57-
66, 1977
4. Holmes G H : A form of familial degeneration of the cerebellum. Brain 30:466-489, 1907
5. Jervis GA: Early familial cerebellar degeneration. J Nerv Ment
Dis 111:398-407, 1950
6. Joubert M, Eisenring J, Robb JP, et al: Familial agenesis of the
cerebellar vermis. Neurology (Minneap) 19:813-.825, 1969
7. Kattah JC, Kolsky MP, Guy J, et al: Primary position vertical
nystagmus and cerebellar ataxia. Arch Neurol 40:310-314,
1983
402
8. Malamud N, Cohen P: Unusual form of cerebellar ataxia with
sex-linked inheritance. Neurology (Minneap) 8.261-266, 1958
9. Norman RM: Primary degeneration of the granular layer of the
cerebellum: an unusual form of familial cerebellar atrophy occurring in early life. Brain 63:365-379, 1940
10. Scherer HJ: Beitrage zur pathologischen Anatomie des
Kleinhirns. Gesamte Neurol Psychiatr 145:335, 1933
11. Weber FP, Greenfield JG: Cerebello-olivary degeneration: an
example of heredo-familial incidence. Brain 65:220-228, 1942
12. Weinstein JM, Gleaton M, Weidner WA, et al: Leber's congenital amaurosis. Arch Neurol 41:204-206, 1984
Central Neurogenic
Hyperventilation
in a Conscious Patient
with a Primary Cerebral
Lymphoma
D. E. Bateman,+G. J. Gibson,? P. Hudgson,"
and B. E. Tomlinson*
~~~~~
~
~
The clinical and neuropathologicd findings of a patient
with central neurogenic hyperventilation are described.
The patient had an extensive primary central nervous
system lymphoma but no lesions below the level of the
superior colliculus. The possible mechanism of central
neurogenic hyperventilation is discussed with reference
to the present case and those previously described.
Bateman DE, Gibson GJ, Hudgson P, Tomlinson BE
Central neurogenic hyperventilation in a conscious
patient with a primary cerebral lymphoma.
Ann Neurol 17 402-405, 1985
Central neurogenic hyperventilation (CNH) is defined
as sustained hyperventilation in the absence of any
peripheral stimulus to respiration. The normal consequences of hyperventilation are a reduction of the arterial carbon dioxide tension (PaC02), elevation of the
arterial oxygen tension (PaOJ and serum pH, and a
normal or slightly elevated alveolar-arterial oxygen
tension difference (PCA-af02); the cerebrospinal fluid
(CSF) p H will also be elevated and must be measured
to exclude hyperventilation resulting from an acidic
CSF C47.
-
From the Deparments of 'Neurology and $Neuropathology, Newcastle General Hospital, and the tDepartment of Chest Medicine,
Freeman Hospital, Newcastle upon Tyne, England.
Received Sept 10, 1984. Accepted for publication Sept 14, 1984.
Address reprint requests to Dr Bateman, Wessex Neurological
Centre, Southampton General Hospital, Shirley, Southampton, England SO9 4 X Y .
Arterial Blood Gas Values
Date
PH
PaC02
(mm HgikPa)
HC03(mM)
PaOz
(mm Hg/kPa)
(mm HgikPa)
P(A-a)02
(mm Hg/kPa)
Sept 29
Oct 1
7.61
7.60
1211.6
8h.1
12
8
116/15.5
124116.5
135118
140118.6
1912.5
1612.1
PA02
~~
PaCO, = arterial carbon dioxide tension; PaOz = arterial oxygen tension; PAO, = alveolar oxygen tension; P(A-a)02 = alveolar-arterial
oxygen tension
difference.
C N H is a rare disorder [4}, and none of the previously reported cases completely fulfill these criteria. In
one of Plum’s patients the CSF p H was acidic 141, and
in the other the PaOz (92 to 94 mm Hg) was not
elevated 131. In the case report of Lange and Laszlo
[2}, only the oxygen saturation is given, making it impossible to be certain that the Pa02 was elevated; at
normal levels of oxygenation, oxygen saturation is relatively insensitive to rises in Pa02. Two other reported
cases 11, 6}, although otherwise fulfilling the criteria
for CNH, lack measurement of the CSF pH. Neuropathological examination in the last 3 cases {l, 2,
61 showed tumor infiltration in the lower brainstem,
although in 2 of these patients there was also tumor
elsewhere in the neuraxis [2, 6’1.
We report a case of C N H together with the neuropathological findings in which the strict criteria for
the diagnosis were fulfilled.
Case Report
A 62-year-old widow was admitted to the hospital with a
three-month history of unsteadiness and personality change.
She had also complained of intermittent generalized headaches, and she had lost about 6 kg in weight. For one week
she had been intermittently confused, and on the day of
admission she was found unconscious at the bottom of the
stairs.
O n admission to the hospital the patient was drowsy and
confused with a left hemiparesis. She was noted to be hyperventilating; this was ascribed to long-standing asthma. Over
the next two weeks her condition continued to deteriorate,
and she was transferred to the Regional Neurological Centre
at Newcastle for further investigation. At that time she was
visibly hyperventilating and tachypneic, with a breathing frequency of 26 per minute. She was unable voluntarily to
interrupt her respiration, and the abnormality persisted during sleep. Examination of the chest showed scattered
wheezes but no other evidence of cardiopulmonary disease.
Neurological examination showed no new findings.
Investigations
On admission to the Regional Neurological Centre,
blood count and smear yielded normal findings. Serum
electrolytes (in millimoles per liter) were as follows:
N a C , 130; K + , 2.5; H C 0 3 - , 16; CI-, 102; urea, 6;
creatinine, 180. A computed tomographic head scan
showed a lucency in the region of the right internal
capsule. The chest radiogram was normal.
Arterial blood gas studies conducted with the patient breathing air on two separate occasions two days
apart showed a gross chronic respiratory alkalosis with
a high PaOz and normal calculated P(A-a)02 (Table).
Examination of the CSF showed 31 white blood
cells per cubic millimeter; protein level, 0.21 gm/L;
glucose level, 4.1 mmol/L; and pH, 7.42; CSF cytology
showed 3 blast and several metamyelocyte-like cells. A
bone marrow examination yielded normal findings. It
was impossible to obtain an accurate measurement of
the patient’s ventilatory function because she was unable to control her breathing, but there were no clinical or radiographic features of severe airflow obstruction.
The presence of abnormal cells in the CSF suggested leukemic infiltration of the meninges or a central nervous system (CNS) lymphoma. Cytotoxic therapy and radiotherapy were considered, but it was
decided that the patient was too ill to justify the treatment. She deteriorated and died two weeks later of
a terminal bronchopneumonia, the C N H persisting
throughout.
Postmortem Findings
Both lungs showed a terminal bronchopneumonia
mainly involving the upper lobes. N o other abnormalities were found outside the CNS.
The brain (1,030 gm) showed no visible gross lesions, and none were palpable. There were some minute gray foci up to l mm in diameter over the anterior third of both temporal lobes. Multiple coronal
sections showed several patches of gray discoloration
averaging 0.5 to 1 cm in diameter in the white matter
of the right frontal lobe. An area of partial softening 8
mm in diameter involved the posterior limb of the
right internal capsule. There were no obvious lesions
in the basal ganglia, thalamus, hypothalamus, or brainstem.
Histologically the cerebral lesions were extensive.
The gray foci seen macroscopically were infiltrations of
large numbers of lymphoid cells. In the most affected
regions, “solid” areas of lymphoid cells were present
(Fig l), and similar cells surrounded many small vessels
in the cortex, sometimes reaching the subarachnoid
space (Fig 2). Where perivascular lymphoid collections
were intense, reticulin had proliferated markedly.
Brief Communication: Bateman et al: Central Neurogenic Hyperventilation
403
histological studies, was a primary CNS lymphoma,
probably a lymphoid lymphoma of B cell type.
Fig 1 , Dense infiltration of white matter and a pmuenous space
by lymphoid cells in the right frontal lobe. (HCE; x 50 before
35% reduction.)
Fig 2.Lymphoid cells among vessels at the base of a s.ulc.us in the
right frontal lobe. Infiltrated sabpial cortex is visible at the .upper
and lower margins of the illustration. ( H 6 E ; x 150 bejore
35% reduction.)
Areas of myelin loss were evident in the heavily
infiltrated regions and in small foci in the right optic
nerve, the optic chiasm, and the left parietal white
matter, where cellular infiltration was absent. Beyond
the solid and more scattered lymphoid infiltrates, there
was a widespread increase in rod-shaped microglia,
particularly visible in the cortical and deep nuclear
masses of the right hemisphere but also evident in the
whire matter of the left hemisphere and the entire
hypothalamus and midbrain to the level of the superior
colliculus. Multiple sections showed no lesion of any
kind in the brainstem below that level. Many cells contained abnormal aggregates of IgM. The diagnosis,
based on the site of the tumor, its light and electron
microscopic appearance, and the results of numerous
404 Annals of Neurology
Vol 17 No 4 April 1985
Discussion
Although the patient had a history of asthma, there
were no clinical signs of marked airflow obstruction,
and in the presence of marked asthma, a reduced Pa02
and increased P(A-a)02 would be expected. The
values of 16 and 19 mm Hg for P(A-a)02 are normal
in the face of the considerably raised PaOz. The serum
and CSF pH were elevated, excluding a stimulus to
respiration caused by a metabolic acidosis. The disorder fulfilled all the criteria for CNH.
The neuropathological findings were of extensive
primary CNS lymphoma that had not infiltrated the
brainstem and had produced only mild meningeal involvement. There was, however, extensive microglial
proliferation in the upper brainstem and midbrain. In
3 of the previously reported cases of CNH, neuropathological data are available (1, 2, 61. The patient
described by Lange and Laszlo [2] also had a lymphoma, and there was extensive tumorous involvement of the pons and midbrain, together with a “thin
meningeal coating of cells” and tumor in the left occipital lobe. Of the other 2 patients, one showed a
brainstem glioma (1); the other was also considered to
have a brainstem astrocytoma, although there was also
evidence of tumor in the midbrain and scattered
throughout the neuraxis {b}.Although neuropathological data were not available in Plum’s possible cases,
both patients were considered to have infiltrating neoplasms of the pons (31.
Previous neuropathological evidence has suggested
that destruction of part of the respiratory centers of
the lower brainstem is responsible for CNH. The present neuropathological findings suggest, however, that
direct destruction of the brainstem respiratory centers
is not necessary for the development of CNH.
In view of the failure to reproduce C N H by destructive lesioning in animals, Plum has recently suggested
an alternate mechanism that ascribes C N H to local
stimulation of chemosensitive areas by hydrogen ions
produced by the tumor (31. Local acidification of the
CSF in the region of the brainstem by tumor cells is a
possibility, because meningeal infiltration was present
(although not extensive). The p H of the lumbar CSF,
which contained malignant cells, was elevated. Generally, the cisternd CSF is more alkaline than the lumbar
CSF, and in several cases of meningeal carcinomatosis
reported by Plum and Price {S], this relationship was
not altered. It seems unlikely, therefore, that this is the
mechanism of CNH, especially because C N H is very
rare despite the relative frequency of meningeal carcinomatosis. In view of the multiple lesions found in this
case, it is not possible to suggest alternate mechanisms
of CNH, and its precise cause remains unknown.
References
1. Goulon M, Escourolle R, Augustin P, et al: Hyperventilation
2.
3.
4.
5.
6.
primitive par gliome bulbo-protuberantiel. Rev Neurol (Paris)
121:636-639, 1969
Lange LS, Laszlo G: Cerebral tumour presenting with hyperventilation. J Neurol Neurosurg Psychiatry 28:317-3 19, 1965
Plum F: Mechanisms of "central" hyperventilation. Ann Neurol
11:636-637, 1982
Plum F, Leigh RJ: Abnormalities of central mechanisms. In
Hornbein TF (ed): Regulation of Breathing, Part 11. New York,
Dekker, 1981, pp 989-1067
Plum F, Price RW: Acid-base balance of cisternal and lumbar
cerebrospinal fluid in hospital patients. N Engl J Med 289: 13461351, 1973
Rodriguez M, Baele PL, Marsh HM, Okazaki H: Central neurogenic hyperventilation in an awake patient with brainstem astrocytoma. Ann Neurol 11:625-628, 1982
Brain Neurotransmitter
Abnormalities in Neuronal
Intranuclear Inclusion
Body Disorder
S. J. Kish, PhD,'J. J. Gilbert, MD,f L. J. Chang, MSc,+
L. Mirchandani, BSc,' K. Shannak, BSc,"
and 0. Hornykiewicz, MD*$
Biochemical markers for the major neurotransmitter
systems were measured in the brain of a patient who
died with neuronal intranuclear inclusion disease. A severe nigrostriatal dopamine deficiency constitutes the
basis for the parkinsonian features in the patient. A
marked loss of brain norepinephrine and serotonin was
found in the basal ganglia and hypothalamus. Brain
amino acid (y-aminobutyric acid and glutamate) and
cholinergic (choline acetyltransferase activity) systems
were either normal or less severely affected.
Kish SJ, Gilbert JJ, Chang LJ, Mirchandani L,
Shannak K, Hornykiewicz 0:
Brain neurotransmitter abnormalities in
neuronal intranuclear inclusion body disorder.
Ann Neurol 17:405-407, 1985
Neuronal intranuclear inclusion body disorder (NIID)
is a rare progressive degenerative disease characterized
histopathologically by intranucleat inclusion bodies
From the *Human Brain Laboratory, Clarke Institute of Psychiatry,
Toronto, Ontario, the ?Department of Pathology, Victoria Hospital,
London, Ontario, Canada, and the $University of Vienna, Vienna,
Austria.
Received Jul 2, 1984, and in revised form Oct 8. Accepted for
publication Oct 14, 1984.
Address reprint requests to Dr Kish, Human Brain Laboratory,
Clarke Institute of Psychiatry, 250 College St, Toronto, Ontario,
Canada, M5T 1R8.
consisting of straight filaments 8 to 9 nm in diameter in
the neurons of the central, peripheral, and autonomic
nervous systems and by neuronal loss and gliosis [S].
We now report neurotransmitter-related abnormalities in the brain of the patient with NIID who was
described earlier by Michaud and Gilbert 1121.
Patient and Methods
Case History
A young woman developed learning difficulties 9 years before her death at age 18 years C12). At age 13, she developed
rigidity, tremor, excessive salivation, shallow and weak voice,
and progressive cognitive impairment (parkinsonian features). In the last 2 years her condition rapidly deteriorated;
she was anarthric and dysphagic, and had dystonic extension
of the head and neck. Before death she had become a spastic
quadriplegic, with emaciation and no voluntary movements.
The immediate cause of death was said to be respiratory
distress.
At postmortem examination (6 hours after death) one half
of the brain was frozen at -80°C for biochemical analysis
and the remaining half was fixed with formalin for histological study.
Neuropathological analysis of one half brain revealed
neuronal cell loss, gliosis, and intranuclear inclusions especially involving the globus pallidus, subthalamic nucleus, substantia nigra (which was depigmented), and red nucleus. The
cranial nerve nuclei, brainstem tegmentum, raphe nuclei, and
locus ceruleus were mildly to moderately affected.
Neurochemical Measurements
Dopamine, norepinephrine, homovanillic acid, serotonin (5HT), and 5-hydroxyindoleacetic acid (5-HIAA) were measured using minor modifications of the high-performance
liquid chromatography (HPLC)-electrochemical method of
Felice and co-workers [53. Amino acids (y-aminobutyric acid
[GABA] and glutamate) were measured using the HPLCfluorometric procedure of Fernstrom and Fernstrom [6}.
Cholineacetyltransferase (CAT) activity was determined according to the methodology of Fonnum [71.
Results and Discussion
In this patient with NIID we found a profound reduction in the concentrations of dopamine and 5-HT,
their metabolites, and also norepinephrine in several
regions of the basal ganglia and diencephalon (Table).
In contrast, the concentration of GABA was normal in
the globus pallidus (and also in the neocortex, hippocampus, and amygdala), moderately elevated in the
caudate nucleus ( + 56%) and putamen ( + 4 3 % ) , but
reduced ( - 36%) in the subthalamic nucleus. Glutamic
acid concentrations were within the control range in all
areas examined. CAT activity was normal in the
striaturn, neocortical subdivisions (temporal, parietal,
and occipital), hippocampus, and amygdala (other regions were not examined).
The neurochemical changes are similar in several
respects to those found in the parkinsonian condition.
405
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central, patients, conscious, hyperventilation, neurogenic, primary, cerebral, lymphoma
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