Content uploaded by Graham Young
Author content
All content in this area was uploaded by Graham Young on Dec 14, 2014
Content may be subject to copyright.
NEUROLOGY AND MEDICINE
Neurology and the bone marrow
J D Pollard, GARYoung
Human bone marrow is a fascinating and com-
plex organ. Its major function is to produce and
sustain normal haemopoiesis, and in a normal
adult this entails the production of more than
10
11
cells/day.
The marrow contains most of the multipo-
tent haemopoietic stem cells, and provides an
environment for these cells to diVerentiate into
each of the well recognised peripheral blood
cells (erythroctes, leucocytes, and platelets). In
addition, the marrow nurtures the develop-
ment of B lymphocytes and provides T cell
progenitors which migrate to the thymus and
diVerentiate there into mature T cells.
This brief review is selective and focuses on
the neurological aspects of several bone
marrow disorders—namely, multiple myeloma,
paraproteinaemia, Waldenstrom’s macroglobu-
lin, cryoglobulinaemia, and lymphoma.
Neurological aspects of bone marrow trans-
plantation and chemotherapy are also consid-
ered.
Multiple myeloma
Multiple myeloma is the most common of the
plasma cell dyscrasias, which also include
monoclonal gammopathies of unknown signifi-
cance (MGUS or paraproteinaemias), plasma-
cytomas, and plasma cell leukaemia. These
terms represent a range of diseases character-
ised by a monoclonal proliferation of plasma
cells, and associated with a corresponding
diversity in clinical behaviour.
Antibody molecules, the product of plasma
cells, are composed of two heavy and two light
chains. There are five heavy chain isotypes (G,
M, A, D, and E) and two light chain isotypes (ê
and ë). Each chain consists of a constant region
and a variable region. The second provides the
recognition site for the antibody molecule; its
structural uniqueness or idiotype derives from
a particular clone of cells as each antibody is
produced by a single clone. Serum electro-
phoresis produces a broad peak in the ã region,
which is composed of a very large number of
immunoglobulin molecules each specified by a
unique plasma cell clone. In patients with mul-
tiple myeloma and other plasma cell dyscrasias
a sharp spike or monoclonal (M) component is
found within the ã region; this M protein rep-
resents a single protein, the product of a single
clone of cells. Immunoelectrophoresis may be
used to show that the M component is
composed of a single light and heavy chain
type—that is, it is truly monoclonal. The
amount of M protein in a given patient
provides a reliable measure of tumour burden
and is thus a useful measurement. Bence Jones
proteins, which represent free light chains, are
produced in excess and excreted in the urine in
50% of cases of multiple myeloma.
Multiple myeloma is a relatively rare cancer,
which occurs predominantly in patients over
60 years of age, although a few patients can
present in their 20s and 30s. The disease is
characterised by a triad of features; lytic bone
lesions, the production of a monoclonal parap-
rotein, and an increase in abnormal plasma
cells in the bone marrow. Associated features
may be bone pain, renal impairment, anaemia,
and hypercalcaemia. Even with modern treat-
ment regimens, including bone marrow trans-
plantation, the disease is essentially incurable,
with median survival being about three years,
although some patients will succumb very
quickly and a few will survive beyond 10 years.
Patients with multiple myeloma are com-
monly referred for neurological opinion be-
cause of frequent involvement of the nervous
system.
INVOLVEMENT OF NERVE ROOTS AND SPINAL CORD
The commonest presenting symptom of multi-
ple myeloma is bone pain. It has been reported
in 80% of cases and in 60% it is located in the
back, most commonly in the lumbosacral
region (fig 1).
1
Radicular pain aZicts one in
five patients. Compression of the spinal cord or
nerve roots also aVects about 20% of cases.
12
The thoracic region of the spinal cord is
involved more often than the other areas and
patients with IgA myeloma seem to be at
greater risk of spinal cord compression. Spinal
cord compression with consequent
neurological emergency results from vertebral
collapse or from tumour mass deriving from
vertebrae or an epidural site (fig 2). Solitary
plasmacytomas may occasionally compress the
spinal cord or even a nerve root in which case
severe root pain results with radiographic signs
similar to acute disc prolapse.
Management of cord compression requires
immediate diagnosis so that appropriate treat-
ment may be given before permanent motor or
sensory deficits result. To detect early evidence
of spinal cord compression and to define the
area of involvement neurological assessment
should be followed by emergency radiography
(MRI). Immediate radiotherapy with steroid
cover is usually appropriate therapy and
Journal of Neurology, Neurosurgery, and Psychiatry 1997;63:706–718706
Institute of Clinical
Neurosciences
J D Pollard
Kanematsu
Laboratories, Royal
Prince Alfred Hospital,
NSW, 2006 Australia
G Young
Correspondence to:
Professor JD Pollard,
Institute of Clinical
Neurosciences, University of
Sydney, Blackburn Building
D06, NSW, 2006 Australia.
Received 13 June 1997 and
in revised form 17
September 1997
Accepted 17 September
1997
decompressive surgery is rarely required,
3
except when the diagnosis is uncertain. Local
control of disease can usually be obtained with
a tumour dose of 2000 cGy given over five days
from a
60
Co source.
4
INTRACRANIAL AND CRANIAL NERVE LESIONS
Although the skull bones are commonly
aVected by myeloma, involvement of the brain
is relatively rare. It may, however, result from
lesions within the bony vault or by metastases
in cases of plasma cell leukaemia. Rarely will
the brain or its coverings be the site of solitary
myeloma.
5
The clinical features of intracranial
myeloma depend on the site of involvement but
may include the symptoms and signs of
increased intracranial pressure, papilloedema,
impairment of consciousness, and focal
neurological deficit including cranial nerve
lesions.
Cranial nerve signs may result from the
involvement of cranial nerve foramina in
myelomatous skull base lesions, or from
compression or distortion of nerves by tumour
masses arising from the sphenoid or petrous
bones.
5
The most often involved cranial nerves
are VI, II, V, VII, and VIII.
The diagnosis, if not apparent from the radi-
ology, is facilitated by the examination of the
CSF as all patients with meningeal involvement
show plasma cells within the CSF and the CSF
protein is usually greatly increased.
4
When
meningeal involvement has resulted in im-
paired consciousness or cranial nerve signs, the
outlook is poor but intrathecal drug therapy
may prove beneficial.
3
PERIPHERAL NEUROPATHY
Neuropathy in myeloma is uncommon with a
prevalence in retrospective series of less than
5%
16
but Walsh
7
found clinical evidence of
neuropathy in 13% in a prospective study, and
electrophysiological evidence in 39%.
The neuropathy is most commonly sensori-
motor in type but purely sensory or relapsing
and remitting forms occur.
89
Neuropathy of
gradual onset is usual but it may be acute or
subacute.
10
Cranial nerves may occasionally be
aVected and upper limbs more than lower.
Figure 1 Spinal MRI showing compression collapse of the
vertebral body of T11 and a lytic lesion within T12. The
patient complained of lower back pain.
Figure 2 Spinal cord MRI of a patient with multiple
myeloma showing compression of the cord after collapse of
the third thoracic vertebral body (arrow).
Neurology and the bone marrow 707
Some patients have systemic amyloidosis and
Kyle and Dyck
9
have emphasised the im-
portance of examining appropriate biopsy
tissue as this complication may be the cause of
neuropathy. The diagnosis may be suspected
by the finding of postural hypotension, impo-
tence, pain, carpal tunnel syndrome, or dissoci-
ated sensory loss.
8
Nerve conduction studies and nerve biopsy
most commonly show changes consistent with
axonal degeneration although demyelination
has been occasionally reported.
8
Infiltration of
nerve with plasma cells or amyloid may be
found.
11
Neuropathy in osteosclerotic myeloma
(POEMS syndrome)
Unlike the rarity of neuropathy in the common
osteolytic variety of myeloma, about half the
patients with osteosclerotic myeloma (2% of
cases) present with neuropathy and do so at
any earlier age. The neuropathy is mainly
motor and similar to those of chronic inflam-
matory demyelinating polyneuropathy
(CIDP); it may be part of a syndrome
designated by the acronym POEMS
12
(polyneuropathy, organomegally, endocrinopa-
thy, M protein, and skin changes). POEMS
syndrome is usually seen in the purely sclerotic
or mixed sclerotic and lytic types of myeloma,
but may occur in the lytic form, in patients with
M protein alone (without myeloma), polyclo-
nal protein alone, and rarely in patients with
extramedullary plasmacytomas.
13
CLINICAL FEATURES
Men are aVected more than women (2:1), the
average age of onset being 47 and one in five
cases are younger than 40.
13 14
Patients usually
present with neuropathy, symptoms of which
may precede the diagnosis by one to two years.
The neuropathy is usually a dominantly motor,
sensorimotor neuropathy, which commences
distally and symmetrically and progresses
slowly with proximal spread. Severe weakness
results with more than half the patients being
unable to walk.
13
Cranial nerves are not
aVected but papilloedema may occur. Periph-
eral (pitting) oedema and hyperpigmentation
are common features as are hypertrichosis (the
development of stiV black hair on the extremi-
ties) and skin thickening. Hepatomegaly is a
frequent finding but splenomegaly and lym-
phadenopathy less so. Gynaecomastia, amen-
orrhoea, impotence, and testicular atrophy
occur, finger clubbing and white nails may be
seen in about 50%, and ascites and pleural
eVusion are occasionally seen. Weight loss
occurs early and patients are often wasted and
appear cachectic. Facial lipoatrophy may be
striking.
15
Haemangiomatous proliferation of
small blood vessels in the skin, kidney, brain,
and lymph nodes has been reported.
Nerve conduction studies show moderate to
pronounced slowing of conduction velocity,
and the changes within sural nerve biopsy are
of mixed segmental demyelination and axonal
degeneration.
9121617
Other laboratory findings are unlike my-
eloma; anaemia is rare and polycythaemia may
be present.
16
Hypercalcaemia and renal insuY-
ciency are uncommon, the bone marrow is
rarely infiltrated with plasma cells, and M
components are of modest amount in the
serum and rarely present in urine.
18
The M
protein is usually of the IgG or IgA heavy chain
class and of the ë light chain type.
14
Tests of endocrine function have shown
diabetes mellitus to be present in 50% of
patients
19
and evidence of thyroid, adrenal, or
gonadal failure less commonly. Low serum tes-
tosterone is common and increased oestrogen
has been reported in impotent men.
16
Radiographic skeletal survey is most impor-
tant diagnostically, particularly as 25% of these
patients show no serum or urine protein.
Osteosclerotic lesions, or a mixture of sclerotic
and lytic lesions, are usually seen, or a sclerotic
rim around a lytic lesion.
Lymph node biopsy in some patients has
shown the features of Castleman’s disease or
angiofollicular lymph node hyperplasia.
17 20 21
PATHOGENESIS OF NEUROPATHY
The cause of neuropathy in patients with
myeloma remains unclear. Binding of immu-
noglobulin to neural components has been
described in only some cases.
22 23
Reactivity of
M components to myelin would be an
attractive hypothesis in the demyelinating neu-
ropathy seen in osteosclerotic myeloma, but
has been shown infrequently.
17
Recent evidence implicates a role for cy-
tokines in some aspects of POEMS syndrome.
Bone destruction in myeloma is contributed to
by cytokines such as tumour necrosis factor â
(TNF-â) and interleukin 1b (IL-1b), which act
as osteoclastic activating factors.
24 25
Increased
concentrations of TNF-á have been found in
the serum of patients with POEMS and early
weight loss
15
and have been proposed as a pos-
sible cause of the pronounced wasting. In-
creased concentrations of IL-1 and IL-6 have
also been found in POEMS syndrome
15
and in
Castleman’s disease increased serum concen-
trations and production of IL-6 by lymph node
cells have been found.
26
Several workers have
proposed an angioproliferative factor to ac-
count for the proliferative changes described in
small blood vessels.
17 27
These factors may also
play a part in the neuropathy as TNF-á and
IL-1 have been implicated in increased vascu-
lar permeability and TNF-á has been shown to
be eVective in blood-nerve barrier
breakdown.
28
Compromise of the blood-nerve
barrier is clearly a prerequisite for circulating
immunoglobulin to react with myelinated
nerve fibres.
TREATMENT
The neuropathy complicating multiple my-
eloma does not usually respond to therapy with
either plasmapheresis, cytotoxic drugs, or a
combination of these
39
although there are
occasional reports of benefit.
29
Some cases
associated with solitary plasmacytoma have
improved after radiotherapy.
16 30
Kyle and Dyck
9
recommend radiotherapy
(40–50 cGy) for patients with single or
multiple osteosclerotic lesions in a limited area
708 Pollard, Young
and have found substantial improvement of the
neuropathy in more than 50%. The improve-
ment may be slow. In patients with widespread
lesions chemotherapy is advised (melphalan
and prednisone).
9
The combination of pred-
nisone and cyclophosphamide has also been
documented to benefit the neuropathy in some
patients with POEMS syndrome.
13 17 31
Neurological complications of
paraproteinaemia
Monoclonal components may be detected in
patients with conditions other than multiple
myeloma or plasma cell dyscrasias. They may
occur in lymphoid and non-lymphoid neopla-
sia and various autoimmune conditions.
Moreover, they may be seen in the absence of
any recognisable disease. These cases are clas-
sified as MGUS. The second phrase recognises
the need for long term follow up of these
patients. Such benign paraproteins occur in
about 3% of the population but the incidence
increases with age.
Peripheral neuropathy associated with
MGUS
Several early case reports described an associ-
ation between neuropathy and IgM parapro-
teins. Kahn et al
32
first demonstrated a clear
statistical relation between neuropathy and the
presence of paraproteins. They studied 14000
serum samples from patients referred to a
neurological centre. Fifty six patients had
MGUS and 16 of these had neuropathy. The
report by Latov et al
33
which showed binding of
IgM to the myelin sheath in a patient with a
demyelinating neuropathy stimulated intense
interest and was confirmed by other
workers.
34–37
Although IgG paraproteins are the
most common, neuropathy is more often seen
in patients with IgM paraproteinaemia. In a
series of 7004 patients with MGUS from the
Mayo Clinic 74% had IgG, 15% IgM, and 11%
IgA paraproteins. In this group 65 patients had
neuropathy; 48% of those patients had IgM
paraprotein, 37% IgG, and 15% IgA.
38
Among
62 patients with neuropathy and MGUS
reported by Yeung et al,
39
the paraprotein class
was IgM in 46, IgG in 11, and IgA in five. Kelly
et al
40
found that 10% of 279 patients with neu-
ropathy without underlying systemic disease
(alcohol, diabetes, etc) had an M protein on
serum electrophoresis. Six per cent had
MGUS, 2.5% primary amyloid, 1.1% my-
eloma, and there was one patient each with
Waldenstrom’s macroglobulinaemia and heavy
chain disease.
Neuropathy associated with IgM
paraproteinaemia
CLINICAL FEATURES
The neuropathy usually presents as a slowly
progressive distal sensorimotor neuropathy,
predominantly aVecting men
36 38 39
in the sixth
or seventh decade. Very occasionally the course
is relapsing and remitting and the symptoms
and signs purely sensory. Multifocal neu-
ropathy has rarely been found.
39
Sensory
symptoms predominate at onset and ataxic and
upper limb postural tremor are prominent
features.
36 38 39
LABORATORY INVESTIGATIONS
The CSF protein is often raised and motor
conduction velocity reduced to levels within
the demyelinating range.
36
A characteristic
finding is that of considerable prolongation of
distal motor latencies representing a large distal
accentuation of conduction slowing.
41
Pathological changes in peripheral nerve are
characterised by demyelination and fibre loss.
Fibre loss is often considerable. Inflammatory
infiltrate as usually lacking but hypertrophic
changes are occasionally seen.
37 42
Electron microscopy has shown in many
cases widened myelin lamellae between major
dense lines, most pronounced in the outer
myelin lamellae (fig 3).
36 37 42
The evidence
suggests that this change results from the
deposition of the paraprotein, and it is particu-
larly pronounced in perinodal regions and
Schmidt Lantermann incisures, where the
antigenic target, myelin associated glycopro-
tein, is located.
43
An interesting finding is that
on teased fibre preparations tomacula (focal
areas of hypermyelination) may be seen,
44
a
finding characteristic of hereditary sensitivity
to pressure palsy, due to a deletion within the
gene for PMP-22.
IMMUNOPATHOLOGY: PARAPROTEIN SPECIFICITY
IgM binding to surviving myelin sheaths has
been shown by both direct and indirect
immunofluorescent techniques.
22 45
Latov et al
first showed that the antigenic target of some
IgM paraproteins was myelin associated glyco-
protein ,
46
a finding confirmed by others.
37 47 48
These antibodies have a similar specificity to
the murine monoclonal antibody HNK-1
which recognises a carbohydrate epitope on
other glycoprotein and glycolipid molecules
within nerve
49
: PO glycoprotein,
50
PMP22
glycoprotein, the glycolipids sulphated glu-
curonic acid paragloboside (SGPG), sulphated
glucuronic acid and lactosaminyl paraglobo-
side (SGLPG),
49
and several cell adhesion
molecules, N-CAM, LI, and JI glycoprotein.
51
However the patients’ IgM antibodies have a
higher aYnity for myelin associated glycopro-
tein than the other glycoproteins
52
and react
poorly with several of the other molecules. The
use of specific antihuman IgM antibodies to
detect the IgM paraproteins deposited in vivo
has shown these mainly in the periaxonal and
the outer rim of the myelin sheath, Schmidt-
Lantermann incisures, and paranodal loops—
that is, the region of myelin associated
glycoprotein localisation. About 50% of IgM
paraproteins associated with sensorimotor
neuropathy react with myelin associated
glycoprotein.
53
IgM paraproteins may also react with GM-I
gangliosides. Monoclonal or polyclonal IgM
anti-GM-1 antibodies have been reported in
association with a motor neuropathy with con-
duction block and motor neuron disease.
54–56
Most of these antibodies show specificity for
the terminal Gal (â1–3) Gal Nac structure.
Neurology and the bone marrow 709
Other antibodies show specificity for the
disialosyl groups on gangliosides GD1b,
GT1b, GQ1b, and others. Patients with these
antibodies present with a progressive ataxic
neuropathy with involvement of large sensory
fibres.
57
Patients with chronic sensory neu-
ropathy have also been described with parapro-
teins reacting to chondroitin sulphate
58
and
sulphatide.
56
The pathological changes in these
cases is axonal degeneration.
THE ROLE OF ANTIMYELIN ASSOCIATED
GLYCOPROTEIN
(MAG) ANTIBODIES
The mechanism by which these antibodies
cause demyelination may not be clearly under-
stood until the role of myelin associated glyco-
protein is more clearly defined. However there
is accumulating evidence that the antibodies
are pathogenic. As described above IgM can be
demonstrated in situ in regions of myelin asso-
ciated glycoprotein localisation. Focal demyeli-
nation was produced by intraneural injection of
antibody into the sciatic nerve of the appropri-
ate species.
59
Tatum
60
has produced the electro-
physiological and pathological features of the
disease by passive transfer studies into new-
born chicks, which have a defective blood-
nerve barrier. The question of how the
antibodies cross the blood-nerve barrier in
humans remains unanswered, but the electro-
physiological findings of Kaku et al
41
of distal
slowing, suggest that the antibody leaks into
nerve preferentially from the region of the neu-
romuscular junction where the blood nerve
barrier is known to be deficient. There is there-
fore mounting evidence that the neuropathy
associated with anti-MAG antibody can be
regarded as an autoimmune disorder of nerve.
NEUROPATHY ASSOCIATED WITH IgG AND IgA
PARAPROTEINAEMIA
Although IgG paraproteins are more common
in the community then IgM, neuropathy is
more commonly associated with the IgM.
22 39 45
The course of neuropathy associated with IgG
paraproteins may be chronic progressive or
relapsing and remitting. Five cases of IgG
paraproteinaemia and neuropathy were de-
scribed by Bleasel et al
62
; they followed a
relapsing and remitting course and were in all
respects, apart from the monoclonal protein,
similar to cases of chronic inflammatory demy-
elinating polyneuropathy (CIDP). Although
binding of IgG or IgG light chain fragments to
the myelin sheath has been demonstrated in a
few cases
22 61
evidence for reactivity to defined
myelin antigens is lacking. Three cases with
sensorimotor axonal neuropathies have been
described with IgG antibody reactive to neuro-
filament determinants.
62
Relatively few cases of neuropathy associated
with IgA paraproteinaemia have been de-
scribed. In the series of Gosselin et al
38
there
were 10 patients in whom the clinical features
were similar to cases of IgG and IgM parapro-
teinaemia neuropathy. Three separate patients
have been described in whom IgA paraprotein-
aemia was associated with a motor neuron-like
disease.
22 63 64
Hays et al
65
reported a similar
patient in whom the IgA paraprotein reacted to
a neurofilament antigen.
TREATMENT
There is general agreement that patients with
neuropathy associated with IgG and IgA para-
proteins respond to therapy—either plasma
exchange, intravenous immunoglobulin, or
immune suppression (steroids with or without
azathioprine or cyclophosphamide).
93961
The
eYcacy of treatment in patients with IgM asso-
ciated neuropathy remains controversial. Ben-
efit has been reported in several uncontrolled
studies
29 33 63
but not in a controlled trial.
966
Other centres with considerable experience
confirm the disappointing results of treatment
in IgM paraprotein associated neuropathy.
39 67
These patients fortunately progress very slowly
and many may be managed conservatively
without the introduction of potentially danger-
ous therapies (corticosteroids or immune sup-
pression). In patients who progressively dete-
riorate it is our practise to try plasma exchange
or intravenous immunoglobulin and introduce
immunosuppressive agents on a trial basis
(pulse cyclophosphamide or melphalan) only
Figure 3 Electron micrograph of a sural nerve biopsy specimen from a patient neuropathy
associated with IgM paraprotein. Note that outer myelin lamellae (wl) are widened. Bar =
1 µm.
710 Pollard, Young
when the first treatment has failed and if
patients are becoming seriously incapacitated.
Patients in whom monoclonal or polyclonal
antibodies against GM-1 ganglioside are asso-
ciated with a clinical syndrome of multifocal
motor neuropathy with conduction block may
respond to therapy with either intravenous
immunoglobulin or cyclophosphamide.
68
Waldenstrom’s macroglobulinaemia
Macroglobulinaemia results from an uncon-
trolled proliferation of lymphocytes and plasma
cells which produce excessive circulating
monoclonal IgM protein; the bone marrow is
extensively infiltrated with lymphocytes and
plasma cells. Other causes of macroglobulinae-
mia include IgM monoclonal gammopathy of
undetermined significance, lymphoma, chronic
lymphatic leukaemia, and amyloid and IgM
myeloma. The clinical features usually include
weakness, fatigue, and bleeding often of the
oronasal region. Impaired vision, mental con-
fusion, neuropathy and other neurological
symptoms may occur. Dyspnoea and conges-
tive cardiac failure may be evident and enlarge-
ment of spleen, liver, and lymph nodes.
STROKE AND SUBARACHNOID HAEMORRHAGE
Patients may present with sudden fatal cerebral
haemorrhage or with focal brain syndromes, as
a result of the bleeding tendency or from
cerebral ischaemia.
69
The M protein interferes
with the clotting cascade, but a more important
mechanism seems to be an abnormality of the
platelet plug and its formation.
70
ENCEPHALOPATHY: HYPERVISCOSITY SYNDROME
Bing and Neil
71
first described the association
of diVuse CNS disease and hyperglobulinae-
mia. Numerous CNS manifestations have been
described in macroglobulinaemia including
pyramidal tract dysfunction, dizziness, head-
ache, ataxia, tremors, hearing loss, lethargy,
organic psychosis, and coma.
69
Many of these
cases showed retinal change including haemor-
rhages, venous engorgement, papillitis, and
exudates.
72
Pathological studies showed lym-
phocyte and plasma cell infiltration of Virchow
Robin spaces,
73
multiple small haemorrhages
within the brain, and plasma (IgM) exudation
into brain parenchyma and perivascular
spaces.
70
Because of these findings it has been
proposed that these symptoms of diVuse CNS
involvement result from increased viscosity and
altered vascular permeability.
The hyperviscosity syndrome is character-
ised by bleeding, ocular, neurological, and,
rarely, cardiovascular manifestations.
70
Ocular
symptoms include diplopia, blurred vision, and
visual failure. The retinal veins are distended
and tortuous and may assume the form of a
string of sausages. Haemorrhages, exudates,
and papilloedema may occur. Symptoms of
CNS involvement include headache, dizziness,
deafness, unsteadiness, and vertigo, and im-
pairment of consciousness which may progress
to coma or death. The importance of recognis-
ing this syndrome is that treatment of the
hyperviscosity by plasmapheresis can relieve
most symptoms.
70
MYELOPATHY
Spinal cord syndromes (spastic paraparesis or
tetraparesis) may result from the hyperviscosity
changes described above, in addition to the
more common cerebral symptoms and signs.
The spinal cord may be compromised by bony
compression or cellular infiltration. Patients
with macroglobulinaemia and lower motor
neuron syndromes have been described and in
one case signs and symptoms of primary mus-
cular atrophy reversed after treatment with
chlorambucil.
74
PERIPHERAL NEUROPATHY
Sensorimotor peripheral neuropathy occurs
commonly in macroglobulinaemia.
75 76
The
symptoms, signs, and laboratory findings are
essentially the same as those already discussed
for IgM paraprotein associated neuropathies.
TREATMENT
Plasmapheresis is indicated for the symptoms
of the hyperviscosity syndrome. It has been
reported in uncontrolled studies to improve
patients with neuropathy
29 77
but other reports
are unfavourable.
75
Occasional patients have
reportedly benefited from chemotherapy
alone
78
and also from a combination of chemo-
therapy (chlorambucil) and plasmapheresis.
77
There have been no controlled trials.
Cryoglobulinaemia
Cryoglobulins are serum immunoglobulins
which precipitate when cooled and redissolve
when heated. The temperature at which they
precipitate varies but this variable rather than
the amount of protein present, determines
clinical expression of disease.
79
They have been
classified as type 1 (a single monoclonal
protein, IgM, IgG, or IgA), type 2 (a mixture of
monoclonal and polyclonal immunoglobulins),
and type III (polyclonal immunoglobulins
only). Cryoglobulins may occur without evi-
dence of underlying disease (essential cryoglob-
ulinaemia) or be secondary to a lymphoprolif-
erative disorder or a chronic inflammatory or
infective process. A high incidence of antibodies
to hepatitis C virus has been reported in patients
with essential mixed cryoglobulinaemia.
80
The clinical symptoms relate to cold sensi-
tivity and include Raynaud’s phenomenon,
cyanosis or skin ulceration; skin rashes espe-
cially purpura, bleeding from mucous mem-
branes, arthralgia, glomerulonephritis, retinal
haemorrhage, and neurological complications.
COMPLICATIONS OF THE CNS
Transient ischaemic attacks manifested as
transient altered consciousness and coma,
blindness, hemiplegia, and seizures have been
described.
81 82
In such cases stenosis and
occlusion of cerebral vessels without atheroma
have been shown, or changes consistent with
CNS vasculitis. Cerebral infarction has also
been described
83 84
and thrombi of hyaline
acidic material within blood vessels with,
perivascular haemorrhage or multiple throm-
botic occlusions.
84
Neurology and the bone marrow 711
PERIPHERAL NEUROPATHY
Peripheral neuropathy usually presents in the
setting of the typical manifestations of cry-
oglobulinaemia, Reynaud’s phenomenon, cya-
nosis, skin ulceration, and neuropathic symp-
toms are often precipitated by cold weather.
85 86
Neuropathy has been reported in up to 50% of
cases.
87 88
It most commonly presents as a sym-
metric mainly sensory neuropathy with promi-
nent pain and hypaesthesia. Occasionally a
multifocal neuropathy may occur and this may
be superimposed on a symmetric sensory neu-
ropathy. Cranial nerves may occasionally be
aVected and although slowly progressive some
patients show a seasonal remitting and relaps-
ing course.
91
Electrophysiological studies show
impaired sensory conduction and mild slowing
of conduction velocity.
90
Neuropathological studies show mostly ax-
onal degeneration, or axonal degeneration with
some segmental demyelination in teased fibre
preparations.
86
Cryoprecipitation may be seen
within endoneurial blood vessels and within
the vaso nervorum
86
and endoneurial and
perineurial vasculitis have been described.
90
Hence the neurological symptoms and signs in
cryoglobulinaemia probably have an ischaemic
basis, due either to immune complex mediated
vasculitis, or the precipitation of cryoglobulins
within vessels.
TREATMENT
Plasmapheresis is indicated when severe mani-
festations of cryoglobulinaemia are present,
particularly in the early stages. Sustained clini-
cal improvement and reduction of cryoglobulin
concentrations are the end points of therapy.
10
Improvement of both encephalopathy and
neuropathy has been described after treatment
with corticosteroids; combined therapy may be
indicated if vasculitis is suspected. Cold expo-
sure should be minimised.
91
Treatment with
interferon-á may be beneficial in patients with
serological evidence of hepatitis C infection.
80
Malignant lymphoma
Malignant lymphoma is a term used to
describe a heterogenous group of diseases
characterised by a malignant proliferation of
cells of the lymphoid system. Traditionally, two
separate disorders are recognised—Hodgkin’s
disease and the more common non-Hodgkin’s
lymphoma. Hodgkin’s disease typically aVects
lymph nodal tissue, and is characterised by the
presence of large, often multinucleated cells—
the so called Reed-Sternberg cell—which is the
hallmark of this disease. The disease can aVect
the liver and spleen, and, rarely, other organs
such as the skin, the gastrointestinal tract, and
the nervous system. In general, Hodgkin’s dis-
ease represents one of the outstanding success
stories of modern cancer therapy, and even
patients with advanced stage disease can now
expect an 80% chance of 10 year survival.
On the other hand, non-Hodgkin’s
lymphoma is a very heterogenous disease with
a wide variety of clinical presentations and very
varied clinical outcomes. Although lymph
nodal presentation is most common, patients
can often present with extranodal involvement
or, more rarely, with leukaemic manifestations
and marrow failure. Patients may have a very
indolent course requiring little therapy over
periods in excess of 20 years, or have a very
aggressive course with short survival. Currently
non-Hodgkin’s lymphoma is going through yet
another classification debate, epitomised by
proponents of the revised European American
lymphoma (REAL) classification.
Neurological complications may occur when
the disease is active or seems to be in remission.
They result from infiltration of the meninges or
neural parenchyme, compression of spinal cord
or nerve roots, infections of the CNS, or as
complications of treatment. Neurological com-
plications are more common when leukaemic
conversion has occurred and are often seen in
Burkitt’s lymphoma.
LEPTOMENINGEAL LYMPHOMA
Involvement of the meninges usually occurs in
non-Hodgkin’s lymphoma of diVuse rather
than nodular histology
92
and with undiVerenti-
ated cell type.
93
It is more often seen when the
bone marrow or peripheral blood is involved
and in younger patients.
94
Tumour cells may
invade the meninges by haematogenous spread
or by infiltration along perforating blood
vessels from the medullary bone marrow.
95
Tumour masses involving the dura may invade
the subarachnoid space and be disseminated
throughout the spinal fluid pathway.
96
The
meninges of the base of brain and spinal cord
are often involved.
97
The symptoms and signs include those of
increased intracranial pressure and meningitis
aVecting the base of brain and spinal roots;
headache, vomiting, irritability, confusion,
papilloedema, seizures, and cranial nerve and
spinal radicular involvement. Cranial nerves
VII, VI, and III are most commonly aVected.
Involvement of spinal roots may cause pain,
paraesthesiae, or weakness, most often at the
lumbar or sacral level and sphincter dysfunc-
tion and impotence result.
96
Examination of the spinal fluid is mandatory
in making the diagnosis, in particular the dem-
onstration of malignant cells in the CSF.
Raised CSF protein may be found and the glu-
cose may be decreased, but both may be
unaVected.
95
The demonstration of meningeal
enhancement or of enhancing nodules on
nerve roots by MRI, provides suggestive
evidence of meningeal lymphoma, particularly
if infective meningitis can be excluded.
Steroids, intrathecal chemotherapy, and
focal irradiation may each play a part in
therapy. Methotrexate or cytosine arabinoside
are usually given intraventricularly by means of
a CSF reservoir. Radiotherapy may be directed
to clinically or radiographically demonstrated
focal lesions and a combination of radiotherapy
and intrathecal chemotherapy has been shown
to improve survival.
92
EPIDURAL LYMPHOMA
Intracranial, epidural, and subdural lymphoma
occur in less than 10% of cases of Hodgkin’s
disease and non-Hodgkin’s lymphoma.
98
These
lesions may be located over the hemispheres
712 Pollard, Young
but are commonly found at the skull base. Epi-
dural masses may cause focal cerebral lesions,
which will depend on their site (hemiparesis,
dysphasia, altered cognition, or seizures).
There may be headache and other signs of
increased intracranial pressure. Basal
lymphoma may compress cranial nerves or
involve the pituitary and hypothalamus. Sub-
dural lymphoma may present as subdural hae-
matoma as it may be accompanied by fluid
eVusion.
99
Spinal cord involvement by lymphoma
derives either from tumour which invades the
epidural space from paravertebral lymph nodes
through intervertebral foramina, or extension
from lymphomatous vertebral bodies. Com-
pression of the spinal cord by the tumour mass
is usually accompanied by symptoms and signs
of nerve root compression at this level.
Occasional intramedullary invasion may result
from tumour growth along nerve roots. The
symptoms and signs are those of back and
nerve root pain followed by the features of spi-
nal cord compression: weakness, sensory, and
sphincter disturbances. Early diagnosis and
treatment are essential to prevent permanent
disability, and to provide the optimum chance
for recovery. MRI and CSF examination are
indicated to confirm the diagnosis and localise
the area of involvement; therapy consists of
high dose steroids when this complication is
suspected followed by radiotherapy on radio-
graphic confirmation. Surgical decompression
is rarely indicated except when the diagnosis is
uncertain or other complications—for exam-
ple, epidural abscess—are suspected.
INTRACRANIAL LESIONS
Mass lesions intracranially are more common
in patients with non-Hodgkin’s lymphoma but
the overall incidence is low.
96 98
They mostly
derive from meningeal deposits but haematog-
enous metastases do occur.
The symptoms and signs depend on the site
of the lesion and the diagnosis should be con-
firmed by CT and MRI and sometimes
stereotactic biopsy. These lesions are often
responsive to steroids and radiotherapy but if
the meninges are involved intrathecal chemo-
therapy may be indicated.
PERIPHERAL NEUROPATHY
Clinical evidence of neuropathy is uncommon
(8%) but when electrophysiological studies are
used a higher incidence (35%) may be shown.
7
Several diVerent clinical types of neuropathy
are recognised.
SENSORIMOTOR NEUROPATHY
Acute polyneuropathy of the Guillain-Barré
type occurs in patients with lymphoma, more
commonly in patients with Hodgkin’s
disease.
100
Lisak et al
100
found abnormal im-
mune responses in their patients and suggested
that immune suppression predisposed to the
occurrence of the neuropathy. The pathologi-
cal changes are typical of Guillain-Barré
syndrome. Subacute neuropathy has been
described mainly in non-Hodgkin’s lymphoma
and is usually accompanied by lymphomatous
infiltration of peripheral nerves and nerve
roots.
Relapsing and remitting neuropathy is rare
in patients with lymphoma. Pathological stud-
ies in these cases have shown macrophage
mediated demyelination and axonal loss. Sen-
sorimotor neuropathy associated with
lymphoma usually follows a chronic progres-
sive course. It may precede or follow the diag-
nosis of lymphoma.
101
Axonal degeneration and
segmental demyelination have been reported,
with occasional evidence of microvasculitis.
102
SUBACUTE MOTOR NEUROPATHY
A subacute asymmetric lower motor neuron
syndrome, aVecting primarily the lower limbs,
has been described. It may spontaneously
remit. Pathological studies showed anterior
horn cell degeneration and motor root
demyelination
103
but no tumour infiltration or
inflammation.
SENSORY NEUROPATHY
Few cases of sensory neuropathy complicating
lymphoma have been described. The patho-
logical changes are similar to those described in
sensory neuropathy complicating carcinoma.
Because mediastinal lymph nodes are often
involved in Hodgkin’s disease the recurrent
laryngeal nerve, phrenic nerve, and sympa-
thetic chain may be compromised by local
tumour masses.
LYMPHOMA ASSOCIATED WITH HIV
The neurological manifestations of HIV/AIDS
infection are protean, and can involve any
component of the nervous system.
104
The
disorders include HIV dementia, CNS infec-
tion and neoplasms, vascular complications,
peripheral neuropathies, and myopathies.
The primary CNS lymphoma associated
with HIV/AIDS infection has attracted consid-
erable attention
105
not only because of its
increasing incidence but also because of its
interesting biology. It seems that all cases of
primary lymphoma associated with HIV have
integration of the EBV genome into the malig-
nant cells,
106
raising the prospect of an
aetiological role for the EBV virus. Patients
often present with memory loss, confusion, and
lethargy, but may also present with epilepsy.
Radiology shows one or more contrast enhanc-
ing lesions which may be diYcult to diVerenti-
ate from toxoplasmosis. In practical terms this
disease continues to have a poor prognosis.
107
Bone marrow transplantation
Neurological complications occur in about
70% of patients with allogeneic bone marrow
transplantation.
108
The immunosuppressive regime which usu-
ally consists of cyclophosphamide and low dose
total body irradiation rarely produces
neurological complications. However, because
of the underlying disease process and myeloab-
lative therapy, patients undergoing bone mar-
row transplantation are usually severely immu-
nosuppressed and hence prone to infection.
Within the first month, when patients are
Neurology and the bone marrow 713
granulocytopenic, bacterial, viral, or fungal
infections may occur. Despite engraftment
patients remain immunologically compro-
mised for up to one year and are prone to viral
(particularly cytomegalovirus) and protozoan
infection (especially toxoplasmosis).
109
A major complication after allogeneic bone
marrow transplantation is graft versus host dis-
ease (GVHD), in which immunologically com-
petent donor lymphocytes attack host tissue.
Chronic rather than acute GVHD is associated
with neurological complications. Chronic neu-
romuscular disorders are prominent among
these. Polymyositis indistinguishable from idi-
opathic polymyositis is well described.
110 111
It
responds to treatment directed to the
GVHD—that is, immunosuppression.
Myasthenia gravis, accompanied by raised
concentrations of acetylcholine receptor anti-
body and responsive to anticholinesterase
and immunosuppressive agents is also well
described.
112
Peripheral neuropathy has also been re-
ported. The features described are those of
CIDP,
113 114
and most cases have responded to
immunosuppressive agents.
Although there have been reports in which
the patients with GVHD have shown lym-
phocytic infiltration within the brain no recog-
nised pattern of disease has emerged for CNS
involvement.
115
An interesting animal model of
GVHD has been described in which massive
lymphocytic infiltration occurs within the brain
accompanied by pronounced upregulation of
MHC class I and II molecules.
116
No human
equivalent of this condition has been de-
scribed.
Cerebral infarction resulting from infective
endocarditis or non-bacterial thrombotic en-
docarditis has been reported in about 10% of
necropsy series of patients with BMT. The rea-
sons for this complication are unknown.
117
Neurological complications of treatment
It is important to remember that neurological
signs and symptoms in patients with haemato-
logical disorders may result from infection or
complications of therapy.
Radiation therapy
Radiation therapy which is so eVective in the
management of lymphoma, unfortunately has a
wide variety of neurological adverse reactions.
The brain, spinal cord, or peripheral nerve may
be aVected. Tissue damage is to some degree
dose dependent but there is also an idiosyn-
cratic element. Concomitant chemotherapy
and systemic illness may increase the suscepti-
bility to radiation damage.
94
The combination
of cranial irradiation with high dose
intravenous or intrathecal methotrexate is par-
ticularly associated with an increased occur-
rence of encephalopathy, which may take the
form of a disseminated necrotising leukoen-
cephalopathy. This is seldom seen with doses of
irradiation <2000 cGY.
118
ENCEPHALOPATHY
Encephalopathy is more likely to develop if
methotrexate is given during or after cranial
irradiation and it has been proposed that the
second damages the blood-brain barrier allow-
ing methotrexate more ready access to the
brain parenchyma.
118
Acute, subacute, or
chronic encephalopathy, myelopathy, or pe-
ripheral neuropathy may occur. Acute en-
cephalopathy usually occurs within the first
week of therapy and produces lethargy, fever,
headache, nausea, and vomiting. It responds to
corticosteroid therapy and may be due to
radiation induced cerebral oedema. A subacute
encephalopathy occurring after several weeks is
much less common and presents with head-
ache, drowsiness, seizures, nausea, vertigo and
ataxia, and brain stem or cerebellar features. It
usually improves spontaneously but may be
aided by corticosteroid therapy. White matter
changes are evident on MRI or CT. Delayed or
chronic encephalopathy is more common and
may present with focal defects, progressive
dementia, apraxia, or seizures. PET is helpful
in diVerentiating this condition from intracra-
nial malignancy. The pathological changes
include mineralising microangiopathy, dis-
seminated necrotising. leukoencephalopathy,
calcification, axonal degeneration, and
demyelination.
94 96
MYELOPATHY
An early transient myelopathy occurring six to
12 weeks after treatment is uncommon and
usually recovers within three to 12 months.
Delayed progressive myelopathy is more com-
mon and may occur from six months to six
years after radiotherapy. Sensory, motor, and
sphincteric symptoms and signs develop re-
lated to the site of involvement. The incidence
may be as high as 15% in patients with Hodg-
kin’s disease.
119
The course is usually inexora-
bly progressive.
PERIPHERAL NEUROPATHY
Peripheral nerves are relatively resistant to ion-
ising radiation. The brachial plexus, however,
may be involved after irradiation of the axilla or
cervical nodes. The clinical features are of
painless progressive sensorimotor changes
within the distribution of the plexus. These
changes usually occur from six months to 15
years after irradiation and are usually very
slowly progressive. Pathological changes are
characterised by dense epineurial fibrosis, with
demyelination and axonal loss. Blood vessels
within the area are thickened and hyalinised
with lumen reduction or occlusion.
Infection
Patients with lymphoma have an increased sus-
ceptibility to infection for several reasons;
disease associated impaired immunity, immu-
nosuppressive therapy, splenectomy, and the
insertion of CSF reservoirs and shunts.
BACTERIAL INFECTIONS
There is a well documented association be-
tween lymphoma and Listeria monocytogenes.
120
It usually presents as an acute meningitis but
may be accompanied by brain stem signs.
Gram negative organisms, E coli, Pseudomonas,
714 Pollard, Young
Proteus, and Pneumococcus may also be
responsible.
121 122
FUNGAL INFECTIONS
Fungal and bacterial infections account for
about 40% of CNS infections in lymphoma.
Candida, aspergillus, and cryptococcus are the
most frequent fungi involved.
VIRAL INFECTIONS
Herpes zoster is the most common viral infec-
tion in patients with lymphoma, aVecting about
20% of patients with Hodgkin’s disease at some
time during its course.
123
It may present as
meningitis, encephalitis, myelitis, peripheral
neuritis particularly aVecting the thoracic root
zones, and ophthalmic zoster. The symptoms
and signs are similar to those of zoster in the
general population except that generalised
infection is seen more commonly in patients
with lymphoma.
97
Infection with cytomegalovirus, and toxo-
plasmosis have been reported.
124
The first may
produce encephalitis and retinitis and the sec-
ond encephalitis or focal signs due to mass
lesions.
Progressive multifocal leukoencephalopathy
has often been associated with lymphoma,
125
and was first described by Aström et al
126
in
patients with chronic lymphatic leukaemia and
lymphoma.
Toxic eVects of chemotherapy
ENCEPHALOPATHY
Acute encephalopathy may occur with several
antineoplastic agents used in the treatment
of lymphoma and other bone marrow
malignancies. It is a common side eVect of
L-asparaginase. It may be seen with high dose
intravenous or intrathecal cytosine arabinoside
and methotrexate. Methotrexate therapy may
result in acute, subacute, or chronic encepha-
lopathy. Acute encephalopathy results in confu-
sion, lethargy, and seizures within 24 hours of
treatment and usually recovers fully. BrainMRI
usually shows no change. Subacute encepha-
lopathy presents similarly except that focal signs
may be evident and it occurs days to weeks after
treatment.
117
MRI usually shows increased signal
intensity in the periventricular regions of the
white matter on T2 weighted images and recov-
ery usually occurs spontaneously over a few
days. Encephalopathy after chronic high dose
methotrexate or intrathecal therapy is usually of
gradual onset and neurological deficits persist.
This complication limits the dose or further
treatment. Encephalopathy after vincristine
therapy is rare. SIADH is another rare
complication.
127
CEREBELLAR DYSFUNCTION
Acute and subacute cerebellar dysfunction
(and encephalopathy) may follow high dose
intravenous cytosine arabinoside. Presenting
features include nystagmus and truncal ataxia
followed by dysarthria, confusion and lethargy.
Symptoms usually resolve after stopping the
drug. Loss of Pürkinje cells may be evident on
histological sections of the cerebellum.
128
A
similar syndrome may be seen with
5-fluorouracil.
MYELOPATHY
Transient and permanent spinal cord damage
have been reported after intrathecal adminis-
tration of methotrexate and cytosine arabino-
side but this is a rare complication.
PERIPHERAL NEUROPATHY
Peripheral neuropathy is well known as a com-
plication of vinca alkaloid therapy and its
occurrence is dose related. It is the dose limit-
ing factor in the use of this drug. Sensory
abnormalities may occur but weakness which
develops rapidly is the major manifestation of
the neuropathy. The pathological findings are
those of axonal degeneration.
129
Vinca alkaloids
bind to tubulin, and the antimitotic eVect
results from their action on spindle microtu-
bules in dividing cells. In nerve they cause
microtubular breakdown and hence reduce
axonal transport and result in a “dying back”
neuropathy.
Occasional cases of subacute neuropathy
after high dose intravenous methotrexate have
been described. This neuropathy seems to
resolve over a few days.
Summary
Neurological complications are commonly
encountered in disorders of the bone marrow
and they result from various pathological proc-
esses. Compression of nervous tissue, brain,
spinal cord, or nerve may occur from tumour
masses—lymphoma, myeloma, or after bone
destruction as in myeloma. Neurological dys-
function may result indirectly from aberrant
immune responses. Impaired immunity, which
commonly accompanies bone marrow disease
permits the development of opportunistic
infection within the nervous system of which
herpes zoster radiculitis and progressive multi-
focal leukoencephalopathy are two well recog-
nised examples in patients with lymphoma. On
the other hand, autoantibodies produced by a
dysregulated bone marrow are responsible for
the neuropathy seen in association with parap-
roteinemia, myeloma, and macroglobulinae-
mia. Excess immunoglobulin may result in
hyperviscosity causing multifocal and diVuse
central nervous system symptoms in patients
with macroglobulinaemia. Cryoglobulins may
cause ischaemic symptoms and signs in the
central and peripheral nervous systems due to
precipitation within vessels or because of
immune complex mediated vasculitis. An
increased production of cytokines in addition
to immunoglobulins contribute to the
neurological features associated with POEMS
syndrome. In “graft versus host” disease after
bone marrow transplantation, immunologically
competent donor lymphocytes attack host
tissue, producing chronic neuromuscular dis-
orders including polymyositis, myasthenia
gravis, and chronic inflammatory demyelinat-
ing polyradiculoneuropathy. The treatment of
bone marrow disorders may itself be toxic to
the nervous system; radiation myelitis or neuri-
tis and vincristine neuropathy are examples
Neurology and the bone marrow 715
commonly encountered by the neurologist.
These treatments may also impair a depressed
immune system further favouring opportunis-
tic nervous system infection. Understanding
the mechanism of neurological symptom pro-
duction in bone marrow disorders has in some
instances permitted the development of ra-
tional therapy.
We thank the National Health and Medical Research Council of
Australia and the National Multiple Sclerosis Society of
Australia.
1 Silverstein A, Doniger DE. Neurological complications of
myelomatosis. Arch Neurol 1963;9:534–44.
2 Woo E, Yu YL, Ng M, et al. Spinal cord compression in
multiple myeloma: who gets it? Aust N Z J Med
1986;16:671–5.
3 Alexanian R. Diagnosis and management of multiple
myeloma. In: Wiernik PH, et al,eds.Neoplastic diseases of the
blood. New York: Churchill Livingstone, 1991:453–65.
4 Bergsagel DE, Pruzanski W. Syndromes and special presen-
tations associated with plasma cell neoplasia. In: Wiernik
PH, et al,eds.Neoplastic diseases of the blood. New York:
Churchill Livingstone, 1991:485–500.
5 Spaar FW. Paraproteinaemias and multiple myeloma. In:
Vinken PJ, et al,eds.Handbook of clinical neurology.
Amsterdam: North Holland, 1980:131–81.
6 Henson RA, Ulrich H. Peripheral neuropathy associated
with malignant disease. In: Vinken PJ, et al,eds.Handbook
of clinical neurology. Amsterdam: North Holland, 1970:
131–48.
7 Walsh JC. The neuropathy of multiple myeloma. An electro-
physiological and histological study. Arch Neurol 1971;25:
404–14.
8 Kelly JJ Jr, Kyle RA, Miles JM, O’Brien PC, Dyck PJ. The
spectrum of peripheral neuropathy in myeloma. Neurology
1981;31:24–31.
9 Kyle RA, Dyck PJ. Neuropathy associated with monoclonal
gammopathies. In: Dyck PJ, et al,eds.Peripheral neuropathy.
Philadelphia: WB Saunders, 1997:1275–87.
10 Betourne C, Buge A, Dechy H, et al. The treatment of
peripheral neuropathies in a case of IgA myeloma and one
of mixed cryoglobulinaemia. Repeated plasmapheresis.
Nouvelle Presse Medicale 1980;9:1369–71.
11 Vital C, Vallat JM, Deminiere C, et al. Peripheral nerve
damage during multiple myeloma and Waldenstrom’s
macroglobulinemia: an ultrastructural and immunopatho-
logic study. Cancer 1982;50:1491–7.
12 Bardwick PA, Zvaifler NJ, Gill GN, et al. Plasma cell dyscra-
sia with polyneuropathy, organomegaly, endocrinopathy, M
protein, and skin changes: the POEMS syndrome. Report
on two cases and a review of the literature. Medicine 1980;
59:311–22.
13 Nakanishi T, Sobue I, Toyokura Y, et al. The Crow-Fukase
syndrome: a study of 102 cases in Japan. Neurology
1984;34:712–20.
14 Takatsuki K, Sanada I. Plasma cell dyscrasia with polyneu-
ropathy and endocrine disorder: clinical and laboratory
features of 109 reported cases. JapJClinOnc1983;13:
543–55.
15 Gherardi RK, Chouaib S, Malapert D, et al. Early weight
loss and high serum tumor necrosis factor-alpha levels in
polyneuropathy, organomegaly, endocrinopathy, M pro-
tein, skin changes syndrome. Ann Neurol 1994;35:501–5.
16 Kelly JJ Jr, Kyle RA, Miles JM, et al. Osteosclerotic myeloma
and peripheral neuropathy. Neurology 1983;33:202–10.
17 Donaghy M, Hall P, Gawler J, et al. Peripheral neuropathy
associated with Castleman’s disease. J Neurol Sci 1989;89:
253–67.
18 Driedger H, Pruzanski W. Plasma cell neoplasia with osteo-
sclerotic lesions. A study of five cases and a review of the
literature. Arch Int Med 1979;139:892–6.
19 Stewart PM, McIntyre MA, Edwards CRW. The endocrin-
opathy of POEMS syndrome. Scott Med J 1989;34:520–6.
20 Mallory A, Spink WW. Angiomatous lymphoid hamartoma
in the retroperitoneum presenting with neurologic signs in
the legs. Ann Intern Med 1968;69:305–8.
21 Yu GS, Carson JW. Giant lymph-node hyperplasia, plasma-
cell type, of the mediastinum, with peripheral neuropathy.
Am J Clin Pathol 1976;66:46–53.
22 Chazot G, Berger B, Carrier H, et al . Neurological manifes-
tations in monoclonal gammapathies. Pure neurological
manifestations. Immunofluorescence study. Rev Neurol
1976;132:195–212.
23 Dhib-Jalbut S, Liwnicz BH. Binding of serum IgA of multi-
ple myeloma to normal peripheral nerve. Acta Neurol Scand
1986;73:381–7.
24 Garrett IR, Durie BG, Nedwin GE, et al. Production of
lymphotoxin, a bone-resorbing cytokine, by cultured
human myeloma cells. N Engl J Med 1987;317:526–32.
25 Kawano M, Yamamoto I, Iwato K, et al. Interleukin-1 beta
rather than lymphotoxin as the major bone resorbing activ-
ity in human multiple myeloma. Blood 1989;73:1646–9.
26 Yoshizaki K, Matsuda T, Nishimoto N, et al. Pathogenic sig-
nificance of interleukin-6 (IL-6/BSF-2) in Castleman’s dis-
ease. Blood 1989;74:1360–7.
27 Judge MR, McGibbon DH, Thompson RP. Angioendothe-
liomatosis associated with Castleman’s lymphoma and
POEMS syndrome. Clin Exp Dermatol 1993;18:360–2.
28 Spies J, Bonner JG, Westland KW, et al. Blood nerve barrier
breakdown by activated P2 specific T cells. Brain
1995;118:857–68.
29 Sherman WH, Olarte MR, McKiernan G, et al. Plasma
exchange treatment of peripheral neuropathy associated
with plasma cell dyscrasia. J Neurol Neurosurg Psychiatry
1984;47:813–9.
30 Davidson S. Solitary myeloma with peripheral
polyneuropathy—recovery after treatment. Calf Med 1972;
116:68–71.
31 Berkovic SF, Scarlett JD, Symington GR, et al. Proximal
motor neuropathy, dermato-endocrine syndrome, and IgG
kappa paraproteinemia. Arch Neurol 1986;43:845–8.
32 Kahn SN, Riches PG, Kohn J. Paraproteinaemia in
neurological disease: incidence, associations, and
classification of monoclonal immunoglobulins. J Clin
Pathol 1980;33:617–21.
33 Latov N, Sherman WH, Nemi R. Plasma-cell dyscrasia and
peripheral neuropathy with a monoclonal antibody to
peripheral nerve myelin. N Engl J Med 1980;303:618–21.
34 Kahn SN, Smith IA, Eames RA, et al. IgM paraproteinemia
and autoimmune peripheral neuropathy [letter]. N Engl J
Med 1981;304:1430–1.
35 Leibowitz S, Gregson NA, Kennedy M, et al. IgM parapro-
teins with immunological specificity for a Schwann cell
component and peripheral nerve myelin in patients with
polyneuropathy. J Neurol Sci 1983;59:153–65.
36 Smith IS, Kahn SN, Lacey BW, et al. Chronic demyelinating
neuropathy associated with benign IgM paraproteinaemia.
Brain 1983;106:169–95.
37 Meier C, Vandevelde M, Steck A, et al. Demyelinating
polyneuropathy associated with monoclonal IgM-
paraproteinaemia. Histological, ultrastructural and immu-
nocytochemical studies. J Neurol Sci 1984;63:353–67.
38 Gosselin S, Kyle RA, Dyck PJ. Neuropathy associated with
monoclonal gammopathies of undetermined significance
[comments]. Ann Neurol 1991;30:54–61.
39 Yeung KB, Thomas PK, King RH, et al. The clinical
spectrum of peripheral neuropathies associated with
benign monoclonal IgM, IgG and IgA paraproteinaemia.
Comparative clinical, immunological and nerve biopsy
findings. J Neurol 1991;238:383–91.
40 Kelly JJ Jr, Kyle RA, O’Brien PC, et al. Prevalence of mono-
clonal protein in peripheral neuropathy. Neurology 1981;31:
1480–3.
41 Kaku DA, England JD, Sumner AJ. Distal accentuation of
conduction slowing in polyneuropathy associated with
antibodies to myelin-associated glycoprotein and sulphated
glucuronyl paragloboside. Brain 1994;117:941–7.
42 Pollard JD, McLeod JG, Feeney D. Peripheral neuropathy in
IgM kappa paraproteinaemia. Clinical and ultrastructural
studies in two patients. Clin Exp Neurol 1985;21:41–54.
43 Trapp BD, Quarles RH. Presence of the myelin-associated
glycoprotein correlates with alterations in the periodicity of
peripheral myelin. J Cell Biol 1982;92:877–82.
44 Rebai T, Mhiri C, Heine P, et al. Focal myelin thickenings in
a peripheral neuropathy associated with IgM monoclonal
gammopathy. Acta Neuropathol 1989;79:226–32.
45 Dalakas MC, Engel WK. Polyneuropathy with monoclonal
gammopathy studies of 11 patients. Ann Neurol 1981;10:
45–52.
46 Braun PE, Frail DE, Latov N. Myelin associated glycopro-
tein is the antigen for a monoclonal IgM in polyneuropathy.
J Neurochem 1982;39:1261–5.
47 Nemni R, Galassi G, Latov N, et al. Polyneuropathy in non-
malignant IgM plasma cell dyscrasia: a morphological
study. Ann Neurol 1983;14:43–54.
48 Steck AJ, Murray N, Meier C, et al. Demyelinating
neuropathy and monoclonal IgM antibody to myelin-
associated glycoprotein. Neurology 1983;33:19–23.
49 Ilyas AA, Quarles RH, MacIntosh TD, et al. IgM in a human
neuropathy related to paraproteinemia binds to a carbohy-
drate determinant in the myelin-associated glycoprotein
and to a ganglioside. Proc Natl Acad Sci USA 1984;81:
1225–9.
50 Bollensen E, Schachner M. The peripheral myelin glycopro-
tein P0 expresses the L2/HNK-1 and L3 carbohydrate
structures shared by neural adhesion molecules. Neurosci
Lett 1987;82:77–82.
51 Sorkin BC, HoVman S, Edelman GM, et al. Sulfation and
phosphorylation of the neural cell adhesion molecule,
N-CAM. Science 1984;225:1476–8.
52 Miescher GC, Steck AJ. Paraproteinemic neuropathies. In:
Hartung H, ed. Baillieres Clin Neurol 1996:219–44.
53 Latov N. Antibodies to glycoconjugates in neurological dis-
ease. Clinical Aspects of Autoimmunity 1990;4:18–29.
54 Freddo L, Yu RK, Latov N, et al. Gangliosides GM1 and
GD1b are antigens for IgM M-protein in a patient with
motor neuron disease. Neurology 1986;36:454–8.
55 Latov N, Hays AP, Donofrio PD, et al. Monoclonal IgM
with unique reactivity to gangliosides GM1 and GD1b and
to lacto-N-tetraose in two patients with motor neuron dis-
ease. Neurology 1988;38:763–8.
56 Pestronk A, Li F, GriYn J. Polyneuropathy syndromes asso-
ciated with serum antibodies to sulfatide and myelin-
associated glycoprotein. Neurology 1991;41:357–62.
57 Arai M, Yoshino H, Kusano Y, et al. Ataxic polyneuropathy
and anti-Pr2 IgM kappa M proteinemia. J Neurol
1992;239:147–51.
58 Sherman WH, Latov N, Hays AP, et al. Monoclonal IgM
kappa antibody precipitating with chondroitin sulfate C
716 Pollard, Young
from patients with axonal polyneuropathy and epidermoly-
sis. Neurology 1983;33:192–201.
59 Hays AP, Latov N, Takatsu M, et al. Experimental demyeli-
nation of nerve induced by serum of patients with
neuropathy and an anti-MAG IgM M-protein. Neurology
1987;37:242–56.
60 Tatum AH. Experimental paraprotein neuropathy, demyeli-
nation by passive transfer of human IgM anti-myelin-
associated glycoprotein. Ann Neurol 1993;33:502–6.
61 Bleasel AF, Hawke SH, Pollard JD, et al. IgG monoclonal
paraproteinaemia and peripheral neuropathy. J Neurol
Neurosurg Psychiatry 1993;56:52–7.
62 Fazio R, Nemni R, Quattrini A, et al. IgG monoclonal pro-
teins from patients with axonal peripheral neuropathies
bind to diVerent epitopes of the 68 kDa neurofilament pro-
tein. J Neuroimmunol 1992;36:97–104.
63 Bosch EP, Ansbacher LE, Goeken JA, et al. Peripheral neu-
ropathy associated with monoclonal gammopathy. Studies
of intraneural injections of monoclonal immunoglobulin
sera. J Neuropathol Exp Neurol 1982;41:446–59.
64 Nobile-Orazio E, Barbieri S, Baldini L, et al. Peripheral neu-
ropathy in monoclonal gammopathy of undetermined
significance: prevalence and immunopathogenetic studies.
Acta Neurol Scand 1992;85:383–90.
65 Hays AP, Roxas A, Sadiq SA, et al. A monoclonal IgA in a
patient with amyotrophic lateral sclerosis reacts with
neurofilaments and surface antigen on neuroblastoma
cells. J Neuropathol Exp Neurol 1990;49:383–98.
66 Dyck PJ, Low PA, Windebank AJ, et al. Plasma exchange in
polyneuropathy associated with monoclonal gammopathy
of undetermined significance [comments]. N Engl J Med
1991;325:1482–6.
67 Thomas PK, Willison HJ. Paraproteinemic neuropathies.
In: McLeod JG, ed. Baillieres Clin Neurol 1994:128–47.
68 Nobile-Orazio E. Multifocal motor neuropathy. J Neurol
Neurosurg Psychiatry 1996;60:599–603.
69 Logothetis J, Silverstein P, Coe J. Neurologic aspects of
Waldenstrom’s macroglobulinemia. Arch Neurol 1960;3:
564–73.
70 MacKenzie MR. Macroglobulinemia. In: Wiernik PH, et al,
eds. Neoplastic diseases of the blood. New York: Churchill
Livingstone, 1991:501–11.
71 Bing J, Neel AV. two cases of hyperglobulinemia and
aVection of the nervous system. Acta Med Scand 1936;83:
492–506.
72 MacKenzie MR, Fudenberg HH. Macroglobulinemia: an
analysis for 40 patients. Blood 1972;39:874–89.
73 Bing J, Fog M, Neel AV. Reports of a third case of
hyperglobulinemia with aVection of the central nervous
system on a toxic-infectious basis. Acta Med Scand
1937;91:409–27.
74 Bauer M, Bergstrom R, Ritter B, et al. Macroglobulinemia
Waldenstrom and motor neuron syndrome. Acta Neurol
Scand 1977;55:245–50.
75 Vital C, Deminiere C, Bourgouin B, et al. Waldenstrom’s
macroglobulinemia and peripheral neuropathy: deposition
of M-component and kappa light chain in the endoneu-
rium. Neurology 1985;35:603–6.
76 Nobile-Orazio E, Marmiroli P, Baldini L, et al. Peripheral
neuropathy in macroglobulinemia: incidence and antigen-
specificity of M proteins. Neurology 1987;37:1506–14.
77 Meier C, Roberts K, Steck AJ, et al. Polyneuropathy in Wal-
denstrom’s macroglobulinemia: reduction of endoneurial
IgM deposits after treatment with chlorambucil and
plasmapheresis. Acta Neuropathol 1984;64:297–307.
78 Vital C, Henry P, Loiseau P, et al. Peripheral neuropathies in
Waldenstrom’s disease. Histological and ultrastructural
studies of 5 cases. Ann Anat Path 1975;20:93–108.
79 Kyle RA, Garton JP. Immunoglobulins and laboratory
recognition of monoclonal proteins. In: Wiernik PH, et al,
eds. Neoplastic diseases of the blood. New York: Churchill
Livingstone, 1991:373–93.
80 Apartis E, Leger JM, Musset L, et al. Peripheral neuropathy
associated with essential mixed cyroglobulinemia: a role for
hepatitis C virus? J Neurol Neurosurg Psychiatry 1996;60:
661–6.
81 Hutchinson JH, Howell RA. Cryoglobulinemia. Report of a
case associate with digital gangrene. Ann Intern Med 1953;
38:350–7.
82 Hodson AK, Doughty RA, Norman ME. Acute encepha-
lopathy, streptococcal infection, and cryoglobulinemia.
Arch Neurol 1978;35:43–4.
83 Logothetis J, Kennedy WR, Ellington A, et al. Cryoglob-
ulinemic neuropathy. Incidence and clinical characteristics.
Arch Neurol 1968;19:389–97.
84 Abramsky O, Herishanu Y, Lavy S. Cryoglobulinemia and
cerebrovascular accident. Confinia Neurologica 1971;33:
291–6.
85 Butler WR, Palmer JA. Cyroglobulinemia in polyarteritis
nodosa with gangrene of extremities. Can Med Assoc J
1955;72:686–8.
86 Vallat JM, Desproges-Gotteron R, Leboutet MJ, et al.Cry-
oglobulinemic neuropathy: a pathological study. Ann Neu-
rol 1980;8:179–85.
87 Garcia-Bragado F, Fernandez JM, Navarro C, et al. Periph-
eral neuropathy in essential mixed cryoglobulinemia. Arch
Neurol 1988;45:1210–4.
88 Gemignani F, Pavesi G, Fiocchi A, et al. Peripheral
neuropathy in essential mixed cryoglobulinaemia. J Neurol
Neurosurg Psychiatry 1992;55:116–20.
89 Nemni R, Corbo M, Fazio R, et al. Cryoglobulinaemic neu-
ropathy. A clinical, morphological and immunocytochemi-
cal study of 8 cases. Brain 1988;111:541–52.
90 Konishi T, Saida K, Ohnishi A, et al. Perineuritis in monon-
euritis multiplex with cryoglobulinemia. Muscle Nerve
1982;5:173–7.
91 Abramsky O. Neurologic manifestation of macroglobuline-
mia. In: Vinken PJ, et al,eds.Handbook of clincal neurology,
part 11. Amsterdam: North Holland, 1980:184–8.
92 Recht L, Straus DJ, Cirrincione C, et al. Central nervous
system metastases from non-Hodgkin’s lymphoma: treat-
ment and prophylaxis. Am J Med 1988;84:425–35.
93 MacKintosh FR, Colby TV, Podolsky WJ, et al. Central
nervous system involvement in non-Hodgkin’s lymphoma:
an analysis of 105 cases. Cancer 1982;49:586–95.
94 Paleologos NA. Disorders of white blood cells. In: Goetz
CG, et al,eds.Handbook of clinical neurology. Systemic
diseases. Amsterdam: Elsevier, 1993:345–67.
95 GriYn JW, Thompson RW, Mitchinson MJ, et al. Lympho-
matous leptomeningitis. Am J Med 1971;51:200–8.
96 Henson RA, Urich H. Cancer and the nervous system.
London: Blackwell, 1982.
97 Cairncross JG, Posner JB. Neurological complications of
malignant lymphoma. In: Vinken PJ, et al,eds.Handbook of
clinical neurology. Amsterdam: Elsevier, 1980:27–62.
98 Posner JB, Chernik NL. Intracranial metastases from
systemic cancer. In: Shoenberg BS, ed. Advances in neurol-
ogy. New York: Raven Press, 1978:575–86.
99 McDonald JV, Burton R. Subdural eVusion in Hodgkin’s
disease. Arch Neurol 1966;15:649–52.
100 Lisak RP, Mitchell M, Zweiman B, et al. Guillain-Barre
syndrome and Hodgkin’s disease: three cases with immu-
nological studies. Ann Neurol 1977;1:72–8.
101 McLeod JG. Peripheral neuropathy associated with
lymphomas, leukemias and polycythemia vera. In: Dyck PJ,
et al,eds.Peripheral neuropathy. Philadelphia: WB Saunders,
1993:1591–8.
102 Harati Y, Niakan E. The clinical spectrum of
inflammatory-angiopathic neuropathy. J Neurol Neurosurg
Psychiatry 1986;49:1313–6.
103 Schold SC, Cho ES, Somasundaram M, et al. Subacute
motor neuronopathy: a remote eVect of lymphoma. Ann
Neurol 1979;5:271–87.
104 Simpson DM, Tagliati M. Neurologic manifestations of
HIV infection. Ann Intern Med 1994;121:769–85.
105 Knowles DM. Etiology and pathogenesis of AIDS-related
non-Hodgkins lymphoma. Hematol Oncol Clin North Am
1996;10:1081–9.
106 Cinque P, Brytting M, Vago L, et al. Epstein-Barr virus
DNA in cerebrospinal fluid from patients with AIDS-
related primary lymphoma of the central nervous system.
Lancet 1993;342:398–401.
107 Sparano JA. Treatment of AIDS-related lymphomas. Curr
Opin Oncol 1995;7:442–9.
108 Davis DG, Patchell RA. Neurologic complications of bone
marrow transplantation. Neurol Clinics 1988;6:377–87.
109 Elfenbein GJ, Anderson PN, Humphrey RL, et al. Immune
system reconstitution following allogeneic bone marrow
transplantation in man: a multiparameter analysis. Trans
Proc 1976;8:641–6.
110 Pier N, Dubowitz V. Chronic graft versus host disease pre-
senting with polymyositis. Br Med J Clin Res 1983;
286:2024.
111 Schmidley JW, Galloway P. Polymyositis following autolo-
gous bone marrow transplantation in Hodgkin’s disease.
Neurol 1990;40:1003–4.
112 Nelson KR, McQuillen MP. Neurologic complications of
graft-versus-host disease. Neurol Clin 1988;6:389–403.
113 Maguire H, August C, Sladky J. Chronic inflammatory
demyelinating polyneuropathy: a previously unreported
complicaction of bone marrow transplantation. Neurology
1989;39:410
114 Amato AA, Barohn RJ, Sahenk Z, et al. Polyneuropathy
complicating bone marrow and solid organ transplantation.
Neurology 1993;43:1513–8.
115 Rouah E, Gruber R, Shearer W, et al. Graft-versus-host
disease in the central nervous system. A real entity? Am J
Clin Pathol 1988;89:543–6.
116 Hickey WF, Kimura H. Graft v host disease elicits expres-
sion of class I and class II histocompatibility antigens and
the presence of scattered T lymphocytes in rat central
nervous system. Proc Natl Acad Sci USA 1987;84:2082–6.
117 Walker RW, Allen JC, Rosen G, et al. Transient cerebral
dysfunction secondary to high-dose methotrexate. J Clin
Oncol 1986;4:1845–50.
118 Bleyer WA, GriYn TW. White matter necrosis mineralizing
microangiopathy and intellectual abilities in survivors of
childhood leukemia: associations with central nervous sys-
tem irradiation and methotrexate therapy. In: Gilbert HA,
et al,eds.Radiation damage to the nervous system: a delayed
therapeutic hazard. New York: Raven Press, 1980:155–74.
119 Carmel RJ, Kaplan HS. Mantle irradiation in Hodgkin’s
disease. An analysis of technique, tumor eradication, and
complications. Cancer 1976;37:2813–25.
120 Somasundaram M, Posner JB. Neurological complications
of Hodgkin’s disease. In: Lachner MJ, ed. Hodgkin’s disease.
New York: John Wiley, 1976.
121 Chernik NL, Armstrong D, Posner JB. Central nervous
system infections in patients with cancer. Medicine
1973;52:563–81.
122 Lukes SA, Posner JB, Nielsen S, et al. Bacterial infections
of the CNS in neutropenic patients. Neurology 1984;34:
269–75.
123 GoYnet DR, Glatstein EJ, Merigan TC. Herpes zoster—
varicella infections and lymphoma. Ann Int Med 1972;76:
235–40.
Neurology and the bone marrow 717
