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Chronic idiopathic ataxic neuropathy.

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Chronic Idiopathic Ataxic Neuropathy
Marinos C. Dalakas, MD
Fifteen patients with chronic sensory ataxia caused by a large-fiber sensory neuropathy were studied and followed up
for a period of 17.4 years (range, 4 to 41). When first seen, they had distal paresthesias and sensory ataxia of slow onset
and progression, areflexia, normal strength, and a profound loss of proprioceptive and kinesthetic sensation extending
up to the most proximal joints. Needle electromyogram and motor-nerve conduction velocity findings were normal in
most of the patients and sensory potentials were absent in all. Nerve biopsy showed severe loss of the large myelinated
fibers. Nine patients had a serum monoclonal or polyclonal gammopathy (3 with IgMK, 1 with I g h , and 5 with a
polyclonal increase of IgG, IgA, or IgM), and 8 had elevated cerebrospinal fluid y globulin levels in spite of low normal
total cerebrospinal fluid protein levels. No circulating antibodies to ganglionic neurons were found. Therapy with
immunosuppressants or plasmapheresis was unsuccessful. All patients are disabled and their conditions have continued
to worsen without signs of malignancy or systemic illness during a mean follow-up period of 17.4 years.
Chronic idiopathic ataxic neuropathy is a proprioceptive neuropathy, clinically indistinguishable from the one
associated with carcinoma or pyridoxine abuse due to involvement of the dorsal root ganglia, and could represent a
distinct form of an indolent, slowly progressive sensory neuronopathy (ganglionopathy). Although immunopathological mechanisms may play a role, especially in patients with an associated paraproteinemia, the resistance of such
patients to therapy, the progressive course, and the resemblance of this disorder to other toxic neuronopathies associated with pyridoxine abuse or doxorubicin administration suggest a possible toxic etiopathogenesis.
Dalakas MC: Chronic idiopathic ataxic neuropathy. Ann Neurol 19:545-554, 1986
In most polyneuropathies there is dysfunction in both
sensory and motor nerves. In the early stages of
chronic polyneuropathy the cutaneous sensations are
predominantly affected, and by the time the kinesthetic (proprioceptive) modalities are involved, motor
weakness is almost always present. Pure chronic sensory neuropathies affecting mainly the proprioceptive
sensations and presenting as sensory ataxia with complete clinical preservation of motor power are unusual.
Ataxic neuropathies of this type have been reported in
patients with cancer [ l l , 287 but also in some without
cancer 1341, in patients with cancer plus cisplatin toxicity [27}, in patients with starvation after gastric partitioning for obesity 1231, in patients with pyridoxine
intoxication {42}, and as a residual deficit in some
patients with Guillain-BarrC syndrome after muscle
strength improves [46]. Ataxic neuropathy of acute
onset can be a variant of Guillain-Barre syndrome [2]
and has been reported in three patients shortly after
they received penicillin derivatives 1481.
This report details the clinical manifestations, longterm follow-up (average, 17.4 years from onset) and
electrophysiological, immunological, and histological
studies in 15 patients with a chronic slowly progressive
form of ataxic neuropathy who did not have cancer and
did not develop it. Such cases make up a distinct form
of large-fiber sensory neuropathy, chronic idiopathic
ataxic neuropathy (CIAN), which remains unresponsive to all therapeutic methods and causes severe longterm disability.
From the National Institute of Neurological and Communicative
Disorders and Stroke, National Institutes of Health, Beihesda, MD
20892.
Received July 8, 1985, and in revised form Sept 23. Accepted for
publication Sept 30, 1985.
Materials and Methods
Patients
All patients were studied, after giving informed consent, at
the Clinical Center of the National Institute of Neurological
and Communicative Disorders and Stroke. They had been
referred because of a chronic polyneuropathy and were selected from a large group of patients with chronic polyneuropathies studied during the past eight years. When first
seen, they had slowly progressive unsteadiness of gait, loss of
balance that was worse in the dark, paresthesias, and clumsiness of hands with athetoid movements. Patients with a
history of acute neuropathy, ataxic form of Guillain-Barre
syndrome, or with sensory ataxia as a residual deficit from
Guillain-Barre syndrome 1461 were excluded. None of the
patients had sphincteric involvement, neck pains, or signs of
myelopathy and upper motor neuron dysfunction.
All patients underwent complete neurological and medical
examinations. The polyneuropathy was demonstrated clinically and electrophysiologically and confirmed with muscle
and nerve biopsies. Familial causes of neurological disease
were excluded. None of the patients had features of Friedreich’s ataxia. Other types of neuropathy, such as diabetic,
nutritional, tabetic, toxic, porphyric, amyloid, or vasculitic,
Address reprint requests to Dr Dalakas, BuiIding 36, Room 5DO6,
NIH, NINCDS, Bethesda, MD 20892.
545
Table 1. Clinicd Characteristics of Patients with Chronic Idiopathic Ataxic Netlropathy
Age at
Years of
Muscle
AgelSex Onset (yr) Follow-up Strength
Disturbance of
Proprioceptive
and Kinesthetic
Sensations
Disturbance of
Cutaneous
Sensation
DTRs
1
2
5 91M
66IM
18
48
41
10"
Normal
Normal
Profoundb
Profound
Mild, distally
Mild, distally
Absent
Absent
3
4
5
7 llM
78lM
44
27
13
6OlF
67lM
44
54
16
Normal
Normal
Normal
Normal
Marked
Profound
Marked
Marked
Minimal, distally
Mild, distally
Minimal, distally
Minimal, distally
Absent
Absent
Absent
Absent
8
9
10
7 31M
641F
5 21M
63lM
52
53
43
33
21
9"
30
Normal
Normal
Normal
Normal
Marked
Marked
Marked
Profound
Absent
Absent
Absent
Absent
11
37lF
33
4
Normal
Marked
Mild, distally
Minimal, distally
Minimal, distally
Severe, extending
up to proximal
parts of all extremities
Minimal, distally
12
13
42lF
37lF
30
23
12
14
Normal
Normal
Profound
Profound
Normal
Very minimal, distally
Absent
Absent
14
15
33lM
811F
21
62
12
8"
Normal
Normal
Profound
Profound
Mild, distally
Minimal, distally
Absent
Absent
Patient
No.
6
7
65
13
9
Absent
Other
Pupillary denervation hypersensitivity
...
...
Perioral paresthesia
...
...
Diminished sensation in the distribution of the
trigeminal nerve
Pupillary denervation hypersensitivity
...
Diminished sensation in the distribution of the
trigeminal nerve
...
Perioral paresthesia and
pupillary denervation hypersensitivity
"Follow-up lost thereafter.
bProfound = loss extends up to proximal joints; Marked = loss extends up to elbow or knees.
DTRs = deep tendon reflexes
were ruled out. Serum levels of vitamin B12and folate were
determined and a Schilling's test was carried out in all patients. Patients were screened for cancer or other generalized
systemic illness several times during the course of the neuropathy (average period of study, 17.4 years). Screening for
malignancy included upper and lower gastrointestinal series,
mammogram in female patients, colonoscopy, computed tomography, bone survey, chest roentgenograms, liver and
spleen scans, intravenous pyelogram, and bone marrow examinations. In none of the patients was the neuropathy preceded by administration of antibiotics and no patient was
using or abusing vitamin BGprior to the onset of symptoms.
Electrophysiological and Histological Studies
Electrodiagnostic studies were carried out in all the patients.
Each was studied at least three times, each time by a different
neurologist. Tests of motor and sensory conduction velocities, distal latencies, and amplitudes of the evoked responses
and detailed needle electromyography were performed in all
546 Annals of Neurology Vol 19 N o 6 June 1986
the patients in more than two limbs, according to standard
methods. Surd nerve and muscle biopsies were obtained in
all the patients (except Patient 14, Table 1). One portion of'
the biopsy sample was fresh-frozen in isopenrane cooled to
- 160°C in liquid nitrogen and processed for histochemistry
examination using 10-p-thick frozen sections as described
previously [ 12). Presence of amyloid was examined by crystal violet and Congo red staining 1131 and of metachromatic
material by thionine staining. A portion of the nerve biopsy
was fixed in 2% buffered glutaraldehyde for 36 hours and
postfixed in 1% buffered osmium tetroxide. Samples were
dehydrated in graded concentrations of ethanol and embedded in Epon. Transverse sections (1 to 3 + thick) were
stained with toluidine blue or 1% paraphenylenediamine and
examined by light microscopy. The number and size distribution of myelinated fibers and the number of clusters (clumps
of more than three regenerated fibers) were determined according to the method of Behse and Buchthal [4]. None of
these patients died and autopsy material has not been
studied.
Immunocytochemical and Immunological Studies
Serum and Cerebrospinal fluid samples were analyzed by cellulose-acetateelectrophoresisand agarose gel electrophoresis
as previously described 120). Quantitative immunoglobulins
were determined in serum and cerebrospinal flluid (CSF) by
a nephelometric immunoprecipitation method. Search for
immunoglobulin deposits in the patients’ nerves was performed on 5- to 10-pthick acetone-fixed fresh-frozen sections of nerve biopsies as previously described 112, 151. The
presence of circulating antibodies against nerve components
or neurons was studied by applying the patients’ serum to
frozen sections of normal human nerve, normal sensory ganglia, or spinal cord neurons in an immunofluorescence or
immunoperoxidase technique as described previously [1417). Peripheral blood lymphocyte subsets using monoclonal
antibodies to characterize surface markers for helper/
suppressor cells were studied as previously described [19,
2 1).
Results
Clinical Obseruations
All patients were first seen with a slowly progressive
neurological deficit, which started with mild unsteadiness of gait accompanied by poor balance or with
difficulty in writing and fine motor movements of the
hands. Five patients (Patients 5, 7, 8, 10, and 12; Table
1) had muscle pains and most complained of uncomfortable dysesthesias in the feet and soles early in their
illness. Several patients had dysesthesias in the face.
These symptoms progressed after several years, causing severe clumsiness and incoordination of all h b s
and rendering the patients unable to care for themselves. Eleven patients are now confined to wheelchairs and 4 others are using walkers and need help
coordinating their arms for everyday chores. The
motor strength has remained characteristically normal.
All patients had noticed worsening of their coordination in the dark and emphasized the importance
of visual input for purposeful movements. Several
patients reported frightening experiences of total
incapacitation when they found themselves in the
dark during electric power failures. Apart from the
neurological complaints, their general health was excellent and remained so during the follow-up period,
averaging 17.4 years from onset. All patients had a
steadily progressive course with new signs of worsening noticeable every 6 to 12 months. In some there
were longer periods of “plateau” until their condition
again started to worsen. Patients who became wheelchair-bound after an average period of 14 years from
onset were afflicted by severe deafferentation, and
signs of further progression could not be appreciated.
Normal strength was characteristically seen on neurological examination. Though some patients described
their ataxia as “weakness,” no true muscle -weakness
was observed clinically. One patient (No. 8; Table 1)
had very mild distal weakness of the dorsiflexors of the
feet that was thought to be due to inability to completely activate voluntarily the foot erectors as a result
of peripheral deafferentation. Muscle bulk was normal
except for mild atrophy of the first dorsal interosseus
in a few patients with long-standing disability, thought
to be due to disuse. The most striking abnormality was
the presence of severe sensory loss affecting predominantly the proprioceptive and kinesthetic sensations.
Lght touch, pinprick, and temperature sensations were
slightly to moderately impaired in all patients over the
distal part of their extremities up to the mid-forearm
or knee. Pinprick sensation was often described as delayed rather than absent. Diminished sensation was
also noted over the anterior abdominal wall. In one
patient (No. 12, Table 1) cutaneous sensations were
normal and in another (No. 10, Table 1) the cutaneous
sensory loss extended to the shoulders and hips. In 5
patients (Nos. 6, 8, 10, 13, and 15; Table l), cutaneous
sensation was impaired in several divisions of the trigeminal nerve, and perioral paresthesias were described in 3 (Nos. 6, 10, and 15).
The profound loss of kinesthetic sensation (position
and vibration) was disproportionate to the loss of other
sensory modalities and appeared to be the hallmark of
the clinical picture. In the limbs vibration was absent
or impaired up to the shoulders and up to the knees or
pelvis; position was absent or impaired up to the shoulders and knees. Stereognosis and graphesthesia were
absent distally. There was an obvious pseudoathetosis
of the fingers and wrists of the outstretched arms and
extreme dyssynergia on cerebellar testing, which worsened with eye closure. All patients were unsteady,
with a positive Romberg’s sign (if they could stand
unassisted), and had severe ataxia of gait. Nine (Nos. 1
to 4, 6, and 10 to 13; Table 1) could not stand without
assistance and were confined to a wheelchair. Some
were only able to move by crawling. None of the patients had true cerebellar signs such as titubation, truncal ataxia, or dysarthria. Deep tendon reflexes were
absent and the plantar responses were silent or downgoing. Recurrent nonhealing injuries or trophic
changes in the joints were not noted.
Other neurological signs were also present. Three
patients (Nos. 3, 7, and 10; Table 1) had slow saccadic
eye movements, which could theoretically be explained by a possible lack of proprioceptive input from
the eye muscles (Cogan D, Chu F: personal communication, 1983). Two patients (Nos. 2 and 10) had impaired upward gaze and one (No. 10) had an unexplained left ptosis with Cogan’s lid twitch but no
clinical, electrophysiological, or immunological signs of
myasthenia gravis. Three patients (Nos. 2, 11, and 15;
Table 1) had unreactive small pupils with denervation
hypersensitivity responding to 2.5% methacholine,
suggesting involvement of the ciliary ganglia. One patient (No. 14) had unexplained optic atrophy and anDalakas: Large-Fiber Sensory Neuropathy 547
Table 2. Immunological Abnomalities in Patients with Chronic Idiopathic Ataxic Neuropatby
Patient
No.
1
2
3
4
5
6
7
8
9
Serum Immunoglobulin
Level
Normal
Normal
Normal
Monoclonal IgAK
Normal
Normal
Slightly elevated IgA
Monoclonal I ~ M and
K
threefold elevated IgM
Monoclonal IgMK and fivefold
elevated IgM
Total
CSF
Protein
(mg/dl)
45
52
28
23
34
33
29
31
128
CSF Immunoglobulin
and Bands
Not done
Normal
t y-globulin (13%)"
Monoclonal IgAK band
t IgG 4.9b
t y-globulin (12%)
y-globulin (13%)
t y-globulin (13%)
t
y-globulin (11%); t IgA
fourfold; f IgG fourfold;
monoclonal IgMK band
Monoclonal IgMK band
10
Monoclonal IgMK and fivefold
elevated IgM
105
11
Polyclonal increase of IgG
(twofold) and IgA (1.5-fold)
30
t
12
Polyclonal increase of IgG
(twofold) and IgM
(threefold)
Polyclonal increase of IgG
(twofold)
Polyclonal increase of IgA
(mild) and IgM (onefold)
Normal
29
f y-globulin (17%)
21
t
26
Normal; no bands
19
Not done
13
14
15
"Normal: 5-9%, t : increased.
bNormal: 0.0-3.5 mg/dl.
CSF = cerebrospinal fluid; FANA
=
y-globulin (15%), f CSF
IgG (3.9)
y-globulin (23%)
fluorescent antinuclear antibody; D N A
other (No. 15) had diminished taste. Fasciculations
were noted in 1 patient (No. 7). No autonomic dysfunction such as orthostatic hypotension, cardiac irregularities, or changes in gastrointestinal motility were
noted clinically.
Findings of general physical examination were normal in all the patients. Mean age at onset was 41.5
(range, 18 to 65 years) and mean age at time of study
was 58.4 (range, 33 to 81 years). None developed
cancer or systemic illness during a mean follow-up period of 17.4 years (range, 4 to 41) and they are all
alive. Three patients (Nos. 2, 8, 15; Table 1),were lost
to follow-up after an 8- to 10-year period of observation from the onset of the neuropathy.
Laboratory Findings
Results of routine blood chemistry rests, complete
blood counts, and VDRL, BIZ, folate, and Schilling's
test were all normal. Workup for cancer, as outlined
under Materials and Methods, was repeatedly normal.
X-ray films of the chest revealed a calcified granuloma
in 3 patients. No lytic or sclerotic bone lesions were
548 Annals of Neurology Vol-19 No 6 June 1986
=
Other
...
FANA: 1:20
...
FANA: 1:20
..
..
...
Serum IgMK was an antibody to myelin associated
glycoprotein [301
Serum IgMK was an antibody to peripheral nerve
ganglioside 1271
Positive rheumatoid factor,
negative FANA, DNA,
and ENA
t Sedimentation rate: 98
...
anti-DNA 1:40
...
deoxyribonucleic acid; ENA = extractable nuclear antigen.
detected by roentgenography or bone scan. Two patients (Nos. 13 and 14) had slightly elevated levels of
liver enzymes but no signs of chronic active hepatitis.
Serum creatine kinase concentration was slightly elevated in 2 patients (Nos. 1 and 10).
An abnormal immunoglobulin pattern was noted in
the serum of 9 patients (Table 2). Four had a monoclonal gammopathy (Patient 1 had an I g h and Patients 8, 9, and 10 an IgMK). Five other patients had
polyclonal increases of serum immunoglobulins with a
simultaneous elevation in IgG and IgM levels in 3
(Nos. 11, 12, and 13), a simultaneous increase of IgA
and IgM values in 1 (No. 141, and a slight elevation of
IgA content in another (No. 7). In the 3 patients with
monoclonal IgMK, the total IgM value was also two to
three times above normal. None had Bence Jones protein in the urine. Results of bone marrow examination
in all 10 patients with abnormal serum immunoglobulins (polyclonal or monoclonal) were normal. Screening for amyloid was negative.
Sedimentation rate was increased threefold in 1 patient (No. 12). The fluorescent antinuclear antibody
Table 3. Neuromuscukar Evaluation of 15 Patients with Chronic Idiopathic Ataxic Neuropathy
Patient
No.
Nerve Conduction Studies
Electromyography
Motor
Sensory Muscle Biopsy
1
Normal
Normal
Absent
2
Mild denervation
Normal
Absent
3
Normal
Normal
Absent
4
Normal
Normal
Absent
5
Normal
Normal
Absent
6
7
Normal
Increased number of
long-duration
polyphasics
Notmal
Normal
Absent
Absent
Normal
Few angulated fibers
and type grouping
8
Normal
Normal
Absent
Mild type I1 atrophy
9
Normal
Slow (20-30 d ~ )
with prolonged
distal latencies
Slow (25-30 m / ~ )
Absent
Mild type I1 atrophy
Absent
Few angulated fibers
Marked loss of myelinated axons
Normal
Absent
Normal
Marked loss of myelinated axons
Normal
Absent
Normal
Decreased number of
myelinated axons
Marked loss of myelinated axons
Not done
Decreased number of
myelinated axons
Loss of large myelinated
axons
Mild type I1 atrophy
Loss of large myelinated
axons
Decreased number of
Few angulated fibers
myelinated axons
but no type grouping
Decreased number of
Normal
myelinated axons
Mild type I1 atrophy
Decreased number of
myelinated axons
Normal
12
Increased number of
long-duration
polyphasics
Increased number of
long-duration
polyphasics
Normal
13
Normal
Normal
Absent
Normal
14
Normal
Normal
Normal
Normal
Absent
Absent
Not done
Normal
10
11
15
titer was slightly increased (1 :20) in 3 patients (Nos. 3,
5 , and 14), and another (No. 11) had weakly positive
rheumatoid factor.
CSF Studies
The total protein value was normal or surprisingly low
(and below the expected normal level for the patient’s
age) in 13 of the 15 patients (Table 2); in the remaining 2 (Nos. 9 and lo), the CSF protein concentration
was increased twofold. The y-globulin concentration
was increased in 10 of the 15 patients, including those
with normal or very low total protein values. CSF agarose gel electrophoresis performed in 8 patients (Nos.
4, 5, 7, 9 to 12, and 14) revealed no abnormal bands
except in 3 patients with a serum monoclonal gammopathy who had a single monoclonal band with the
same electrophoretic mobility and specificity as that
of their serum. These bands were identified by
immunofixauon as IgAK (Patient 4 ) or IgMK (Patients
Nerve Biopsy
Not done
Marked loss of myelinated axons and increased epineurial
connective tissue
Marked loss of myelinated fibers
Marked loss of myelinated fibers
9 and lo), as reported previously C201. No increased
immunoglobulin synthesis in the CSF was noted C201.
Electromyographic Studies
Needle electromyography was completely normal with
absence of denervating potentials in 11 patients (Table
3); 3 patients (Nos. 7, 10, and 11) had increased longduration polyphasic units suggestive of reinnervation, and one (No. 2) had mild denervation with
fibrillations and positive sharp waves and signs of reinnervation with long-duration polyphasic units. As
noted previously 1341, some patients could not activate
motor units, despite their normal strength, giving the
impression of an incomplete interference pattern, a
phenomenon that could be due to the abnormality of
movement that follows deafferentation [b, 361.
Sensory potentials were absent in all patients. Motor
nerve conduction velocity was normal in ail but 2 patients (Nos. 9 and 10; Table 3) who had slow conducDalakas: Large-Fiber Sensory Neuropathy 549
B
tion with prolonged distal latencies and prolonged Fwave latencies. F-wave latencies of the tibial and
median nerves examined in 6 other patients (Nos. 3, 6,
7, 1I , 12, and 14) who had normal motor nerve conduction and motor distal latencies were normal. The
amplitude of the motor nerve action potentials was low
in Patient 11 (Table 3 ) suggestive of axonal loss.
Fig l . Sections (1+-thin) stained with toluidine blue from sural
nerve biopsy of patients with chronic idiopathic ataxic neuropathy. Severe loss of the predominantly large myelinated fibers is
noted. Several clusters of small fibers (arrowheads in B) indicative of regeneration were noted in sornepatients. (A x 280 before 20% reduction; B x 160.)
Muscle Biopsy
tients (Table 3), was thought to be due to inactivity and
disuse.
Muscle biopsy, performed on all but 1 patient (No. 14)
and processed for muscle enzyme histochemistry, was
essentially normal. Only 3 patients (Nos. 3, 7, and 10)
had a few small, scattered, angulated fibers, indicative
of denervation, and fiber-type grouping, indicative of
reinnervation. No inflammation or amyloid was present. Mild type I1 fiber atrophy, noted in several pa-
Sural Nerve Biopsy
Sural nerve biopsy was performed in all but 2 patients
(Nos. 6 and 14) and showed moderate to marked loss
of myelinated fibers of all diameters (Table 3), with
loss affecting particularly larger fibers (Fig lA,B). This
was confirmed with counts of the number and diame-
550 Annals of Neurology
Vol 19 No 6 June 1986
Total Number of Fibers: 1173
Endoneurial Area: 0.737 mm2
7100 Fibers 15200 - 8MK)I from
10 Normal Individuals
Mean Endoneuriel Area lmmz 10.65 - 1.26)
i
2
4
6
8
10
12
14
16
DIAMETER (pM)
Fig 2. Histogram of fiber diameter of the sural nerve of a patient
with chronic idiopathic ataxic neuropathy (CIAN) (A) (No.
I I ) . compared with an average of 7,100fibersfrom sural nerve
biop.ries of 10 normal individuals (B),aged 18 to 52 (data of
ProJ F . Buchthal). The total number ofjibers in the patient
with CIAN was 11 73. A selective and severe reduction (64% of
normal) in the number of the large (above 7 k ) myelinatedfibers
is noted.
ter of the myelinated fibers as appears in the histogram
(Fig 2A,B). Clusters of small (less than 7 p,) myelinated
fibers (Fig l), indicative of regeneration, were noted in
3 patients. Signs of regeneration were absent in advanced cases in which the nerve was found to be severely depleted of myelinated fibers with only one to
two small myelinated fibers surviving per fascicle. The
vasa nervorum appeared normal and no inflammatory infiltrates were noted. Nerve-fiber teasing was not
performed.
Immunocytocbemical and Immunocbemical Studies
Search for circulating antibodies to neurons and particularly to sensory ganglia was negative, and none of
these patients’ sera bound specifically to neuronal
perikaryons. Nerve biopsy samples, examined with immunofluorescence, revealed deposits of IgM on the
remaining myelinated fibers in 2 patients (Nos. 9 and
lo) with a monoclonal IgMK gammopathy as previously described 112, 151. The monoclonal IgM was
found to be an antibody to myelin-associated glycoprotein in one of these patients (No. 9 ) and immunoreacted with peripheral nerve gangliosides in an-
other (No. lo), as previously reported 1301. Analysis
of peripheral lymphocytes with monoclonal antibodies
revealed decreased numbers of OKT8+ cells (cells
with suppressor markers) in the 2 IgMK patients (Nos.
9 and 10) as previously described 1181. Subpopulation
of peripheral lymphocytes in 5 other patients (Nos. 1,
3, 4, 11, and 12) was normal.
Treatment and Follow-up
All but 2 patients (Nos. 7 and 14) were treated with
high-dose prednisone (100 mg per day), following the
schedule described previously for patients with chronic
relapsing polyneuropathy 1141. Patients 6, 9, and 12
were also treated with azathioprine, 3 mg/kg of body
weight 1141, and Patients 9 and 10 were treated with
prednisone and chlorambucil as described for patients
with Waldenstrom’s paraproteinemic polyneuropathy
[161. Patients 10 and 12 were also treated with biweekly complete plasma exchanges for three months.
Immunosuppressive therapy was not effective. The
condition of all patients continued to worsen slowly.
At present they are disabled, 10 of them wheelchair-bound. None developed cancer or lymphoproiiferative disorders and none improved spontaneously.
Two patients thought that prednisone had worsened
their neurological deficit and felt better subjectively
when prednisone was stopped.
Discussion
Fifteen patients with chronic sensory polyneuropathy
and normal strength presented with a clinically distinct
picture of sensory ataxia and a generalized, slowly pro-
Dalakas: Large-Fiber Sensory Neuropathy
55 1
gressive proprioceptive defect with pseudoathetosis.
Although the other sensory modalities (i.e., light
touch, pinprick, and temperature sensations) were
slightly affected, including on the face, the term chronic
idiopathic ataxic newopathy was preferred in order to
emphasize the severe and disproportionate loss of proprioceptive sensation. CIAN was easily distinguished
from the other common chronic toxic, metabolic, nutritional, or carcinomatous polyneuropathies because
these almost always present with a stocking-glove type
of cutaneous sensory loss rather than sensory ataxia,
and by the time the sensory loss progresses to affect
the proprioceptive and kinesthetic sensations, motor
weakness is very often present. In contrast to the other
chronic severe neuropathies that cause disability due to
muscle weakness, patients with CIAN had normal
strength but were severely disabled because of a profound loss of kinesthetic sensations.
A classification of the known causes of ataxic
neuropathies is presented in Table 4. Our patients with
CIAN, however, form a unique clinical entity in which
none of the other causative agents that appear in this
classification, such as cancer [ l l , 28), cisplatin chemotherapy [27), pyridoxine toxicity 1427, residual deficits
from Guillain-BarrC syndrome [46], chronic cirrhosis
C87, or family history, were identified during a mean
follow-up period of 17.4 years (range, 4 to 41). Only 4
of the patients had an associated monoclonal gammopathy which is another cause of chronic ataxic neuropathy (Table 4).
According to a recent classification [43, 44}, the
Table 4. Classification of Ataxic Neuropathies
Acute neuropathies
Ataxic or pseudotabetic Guillain-Barre syndrome 12, 3,
24,41, 473
Associated with penicillin administration [48]
Subacute neuropathies
Pyridoxine toxicity {42)
Permanent residual sensory ataxia after recovery of muscle
weakness in patients with acute Guillain-Barr6 syndrome E461
Cisplatin toxicity 127)
Carcinomatous large-fiber sensory neuropathy 11, 28)
Chronic biliary cirrhosis 181
Ataxic tropical neuropathy 1393"
Hereditary neuropathies
Hereditary posterior column ataxia of Biemond [51b
Chronic neuropathies
CIAN [present series]
Associated with paraproteins [present series and 7, 15,20,
35. 37. 451
I
_
"Neuropathy reported in Nigeria possibly due to chronic exposure
to dietary cyanide. This, however, is associated with muscle weakness, optic atrophy, and deafness.
hNeuropathic involvement not clearly documented.
552 Annals of Neurology Vol 19 N o 6 June 1986
term neuronopatby has been introduced to describe peripheral nerve diseases in which the primary neuropathological changes appear in the nerve cell body,
contrasting with those conditions that primarily affect
the axon (axonopathies) or myelin (myelinopathies)
[43, 447. Patients with CIAN had clinical, electrophysiological, and nerve-biopsy morphological features
identical to those of ataxic neuropathy associated with
pyridoxine abuse {42) and cancer [28}, two distinct
neuronopathies involving sensory ganglia. This has
been clearly demonstrated post mortem in patients
with ataxic neuropathy and cancer [28) by the presence of severe degeneration, inflammation, and specific loss of neurons only in the sensory ganglia, without features of central chromatolysis {28), as seen
in cases of primary axonal involvement. Therefore
patients with CIAN could also have a sensory
neuronopathy involving dorsal root and gasserian ganglia (ganglionopathy). Our inability to obtain sensory
potentials in patients with CIAN is also consistent with
the secondary breakdown of peripheral axons expected to occur with degenerating ganglionic neurons.
In contrast, if the centrally directed axons of the primary sensory neurons were affected to a greater degree than the peripheral mons, as in the case of primary involvement of the spinal sensory roots, the
sensory action potential would have been preserved.
The resistance of patients with CIAN to therapy and
their normal motor nerve conduction velocity (in all
but 2 ) are also signs against a myelinopathy. Unlike
ataxic neuropathy with cancer in which CSF protein
concentration is almost always elevated El 1, 281, the
CSF protein level in most of the patients with CIAN
was normal, a finding militating against an inflammatory neuronopathy or radiculopathy . Normal CSF yrotein content was also noted previously in patients with
ataxic neuropathy without cancer {347 and the one
resulting from pyridoxine abuse C42). Normal CSF
protein concentration may therefore be a differentiating sign militating against the presence of carcinoma in
a patient with ataxic neuropathy. High CSF protein
content was found in only 2 of our patients (Table 2),
who had a monoclonal IgMK gammopathy, a condition
often associated with an abnormal blood-CSF permeability and high CSF protein levels [ l S , 20;.
Sensory ganglia appear to contain different subpopulations of ganglionic neurons with selective vulnerability {26, 407. This suggests that the selective involvement of the large myelinated fibers responsible
for the sensory ataxia in patients with CIAN may be
due to selective damage of their respective large primary neurons in the sensory ganglia. A similar hypothesis has been proposed for patients with certain
small-fiber neuropathies and presumed ganglionopathies such as dysautonomia El} or amyloid [227,
where there appears to be selective involvement of the
small ganglionic neurons controlling pain and temperature carried by their respective small fibers 11, 22,491.
The properties that render the ganglionic cell perikaryons selectively liable to destruction may be due to
the absence of blood-brain barrier in the dorsal root
ganglia, permitting constant penetration by exogenous
or endogenous agents f33, 38).
The cause of CIAN is unknown. Although the presence of abnormal serum immunoglobulins in 9 patients and positive antinuclear antibodies, anti-DNA,
and rheumatoid factor in 3 others (Table 2 ) suggests
immunopathological mechanisms, no circulating antibodies to ganglionic neurons or peripheral nerve were
found with the immunocytochemical techniques used.
This is in contrast to the presence of antineuronal antibodies in ataxic neuropathy associated with carcinoma
previously reported [ l o , 25, 501. In 2 of the patients
with CIAN with an IgMK gammopathy (Nos. 9 and
10; Table 2), however, the IgM was an antibody
against myelin-associated glycoprotein (MAG) or ganglioside, as previously described 130, 317. In 8 others
(Table 2 ) an increased CSF y-globulin level, disproportionate to the total low normal CSF protein concentration, was found (Table 2). These findings, suggestive of
possible dysimmune mechanisms, prompted us to start
intensive therapy with high-dose prednisone in 12 patients, combined with azathioprine, chlorambucil, and
plasmapheresis in 4. None of the patients improved.
Neuropathy identical to CIAN or with very
minimal motor involvement has been seen previously
in some patients with IgM paraproteinemic polyneuropathies f7, 1 5 , 20, 3 5 , 37, 457. The monoclonal
IgM in some of these patients is an antibody to MAG
f35, 457 and this was found in one of our patients (No.
9 ) 130). The monoclonal IgM of the other patient in
our series (No. 10) reported separately [31] did not
immunoreact with MAG but was found to bind
specifically to a number of human nervous tissue gangliosides that contained disialosyl groups [311. This
suggests that a subset of patients with CIAN have an
associated IgM paraprotein that often immunoreacts
with human peripheral nerve antigens such as MAG
1301, gangliosides [31], or acidic glycolipids, as we
have recently demonstrated in another series of patients with*IgM paraproteinemic polyneuropathy [291.
Patients with paraproteinemic polyneuropathies are a
heterogeneous group with dysfunction at all levels of
the peripheral nerve from myelin to axon to motor
neuron [37], and it is possible that in a subgroup there
may be predominant involvement of the sensory ganglionic neurons causing chronic ataxic neuropathy. In
the present series, however, the disorder was associated with a monoclonal gammopathy in only 4 patients
with CIAN, indicating that other factors should also be
considered for the manifestation of symptoms in patients with CIAN.
The resistance of CIAN to all known therapeutic
methods and the continuous progression of the disease
for a mean period of 17.4 years suggest an irreversible
destruction of neurons in the dorsal root ganglia, possibly analogous to the necrotizing ganglionopathy reported in doxorubicin-treated rats 197. Furthermore,
the clinical picture of CIAN was identical to the
neuronopathy resulting from pyridoxine abuse E421,
which like doxorubicin causes selective destruction of
the dorsal root ganglionic neurons 19, 32, 43, 441,
raising the possibility that CIAN may also be a form of
toxic neuronopathy. A continued search for causative
and circulating toxic or immunological factors affecting
ganglionic neurons may lead to a better understanding
and possible treatment or prevention of this severely
disabling neuropathy. Autopsy material would be essential to study the pathological changes in the ganglionic neurons, posterior roots, and spinal cord.
I thank Prof. F. Buchthal for the preparation of the nerve biopsy
histometric studies in one patient. I also express my deep appreciation to Prof. J. Prineas for his invaluable suggestions and advice and
for reviewing the manuscript. I also thank Dr. J. Rose for critical
review of the manuscript.
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