DOI: 10.

1093/brain/awh234 Brain (2004), 127, 1993–2009

Neurofibromatosis 1-associated neuropathies:

a reappraisal
Alain Drouet,1,2 Pierre Wolkenstein,6,7 Jean-Pascal Lefaucheur,8 Stéphane Pinson,2,5
Patrick Combemale,2,3 Romain K. Gherardi,9 Pierre Brugières,10 Jeffrey Salama,11 Pascal Ehre,4

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Philippe Decq,6,12 and Alain Créange6,13
1
Service de Neurologie, 2Réseau NF-Rhône-Alpin, 3Service Correspondence to: Professor Alain Créange, Service de
de Dermatologie and 4Service de Radiologie, Hôpital Neurologie, Hôpital Henri Mondor, 51 avenue du Maréchal
d’Instruction des Armées Desgenettes, 5Laboratoire de de Lattre de Tassigny, 94010 Créteil, France
Génétique Moléculaire, Hôpital Edouard Herriot, Lyon, E-mail: [email protected]
6
Réseau NF-Mondor, 7Service de Dermatologie, 8Service de
Physiologie-Explorations Fonctionnelles, 9Département
de Pathologie, 10Service de Neuroradiologie, 11Service de
Neurologie, Hôpital Avicenne, Bobigny, 12Service de
Neurochirurgie and 13Service de Neurologie, Hôpital Henri
Mondor, AP-HP, et Université Paris XII, Créteil, France

Summary
Neurofibromatosis 1 (NF1) is a common disease which is (three), moderate or minor axonal changes (four) or no
a source of various multisystemic manifestations related axonal changes (seven). Four patients had axonal neu-
either to the accumulation of neurofibromas or to spe- ropathies. There was a strong association between the
cific developmental abnormalities. The neurofibroma is presence of a peripheral neuropathy and large root dif-
the hallmark lesion of NF1 and develops from periph- fuse neurofibromas (P < 0.03) and subcutaneous neuro-
eral nerves. However, to date, the description of periph- fibromas (P < 0.0001). Severe morbidity and mortality
eral neuropathies of NF1 has not been investigated. To of patients with NF1 and peripheral neuropathies was
examine this question, we have evaluated 688 NF1 50%, much higher than what is observed in the general
patients for the presentation, prognosis and associated population of patients with NF1, and 100% in patients
morbidity of peripheral neuropathies in two hospital- with the most severe symptoms and electrophysiological
based series. We collected 18 patients (four women changes (demyelination with severe axonal features).
and 14 men) with diffuse peripheral neuropathy Four patients out of 18 (22%) developed a malignant
(2.3%). Eight patients had a paucisymptomatic or an peripheral nerve sheath tumour (MPNST), a much
asymptomatic neuropathy detected only on electrophy- higher proportion than in the whole population of
siological study, two had minor sensory manifestations, NF1. Two patients died. Peripheral neuropathy consti-
five had moderate motor and sensory manifestations and tutes a potentially severe complication in patients with
three had severe motor and sensory manifestations. NF1 associated with a frequent morbidity related to
Superimposed radicular changes were observed in spinal complications and MPNSTs. Association of prox-
seven cases. Two patients had a subacute and 16 a imal large neurofibromas, peripheral neuropathies and
chronic polyneuropathy. Fourteen patients had a demye- subcutaneous neurofibromas may constitute a phenotype
linating neuropathy with either severe axonal changes of NF1 with a severe prognosis.

Keywords: neurofibromatosis 1; peripheral neuropathy; demyelination; malignant peripheral nerve sheath tumour

Abbreviations: FDG = [18F]fluoro-2-deoxyglucose; MPNST = malignant peripheral nerve sheath tumour;

NF1 = neurofibromatosis 1.
Received December 1, 2003. Revised February 28, 2004. Second revision April 19, 2004. Accepted April 23, 2004.
Advanced Access publication August 2, 2004

Brain Vol. 127 No. 9 # Guarantors of Brain 2004; all rights reserved
1994 A. Drouet et al.

Introduction Patients and methods

Neurofibromatosis 1 (NF1) is a common genetic disorder
characterized by multisystemic manifestations related in
Patients
part to the accumulation of neurofibromas. Neurofibromas Patients were selected from two NF clinics, the Réseau NF-
arise from the proliferation of Schwann cells and perineur- Mondor (383 NF1 patients) and the Réseau NF-Rhône-Alpin
ial fibroblasts in nerve and cutaneous nerve endings. Neuro- (305 NF1 patients). All met the diagnostic criteria for NF1
fibromas may be benign, as dermal neurofibromas or according to established criteria (National Institutes of Health
Consensus Development Conference, 1988) The patients

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plexiform neurofibromas, or malignant, leading to consider-
able morbidity and mortality, especially in adults (Leroy were ascertained between June 1995 and June 2002 (Réseau
et al., 2001). Morbidity associated with benign neurofibro- NF-Mondor) and between June 1999 and December 2002
mas is dependent on the location of the lesions. When the (Réseau NF-Rhône-Alpin) using the software of the National
neurofibromas are located in the cutaneous nerve endings, Neurofibromatosis Foundation International Database
the main prejudice is aesthetic. When the neurofibromas (Vancouver, British Columbia, Canada) (Friedman, 1997). All
develop in the subcutaneous nerves, they may lead to patients with NF1 were referred to the NF clinic and examined
chronic disabling pain, considerable dysmorphic changes by a physician specialized in NF1 (P.W. and P.C.) and by a
and may degenerate into malignant peripheral nerve sheath neurologist (A.D. and A.C.) if signs or symptoms of neuro-
tumours (MPNSTs). Intradural neurofibromas located at the logical involvement were present. We selected patients with
proximal part of the spinal roots are a source of nerve root clinical symptoms or signs suggesting peripheral nerve invol-
or spinal cord compressions (Ferner et al., 1989; Riccardi, vement, and included those with electrophysiological signs of
1992). These may cause radicular symptoms, including polyneuropathy. Two additional patients (patients 9 and 18)
pain, weakness or sensory loss, and, moreover, paraplegia with myelopathy have been included after a systematic elec-
and tetraplegia. Finally, some patients may develop mono- trophysiological examination.
neuropathies as a result of nerve compression (Canale et al.,
1964). Despite a considerable range of complications Clinical study
related to peripheral nerve development and associated
Information collected regarding the neuropathy included
tumours in NF1, the prevalence of peripheral nerve involve-
topography of sensory and motor involvement, time course
ment in NF1 is considered rather low in large clinical
and severity of the neuropathy. Severity of the neuropathy was
studies, ranging from 0 to 4.3% of nerve compression
evaluated as follows: –, asymptomatic or paucisymptomatic;
and 0 to 2.5% of spinal root compressions (Huson et al.,
þ , minor sensory manifestations; þ þ , moderate motor and
1988; Riccardi, 1992; Hughes, 1994; Friedman and
sensory manifestations; and þ þ þ , severe motor and sen-
Birch, 1997; Créange et al., 1999; Ruggieri et al., 1999).
sory manifestations. Other neurological abnormalities,
Similarly, few cases of polyneuropathies in NF1 have been
including CNS manifestations, were also recorded.
described (Bielschowsky, 1923; Lambers, 1952; Thomas
The following NF1 manifestations were recorded: location
and Eames, 1971; Bradley et al., 1974; Bosch et al.,
of peripheral neurofibromas, i.e. cutaneous and subcutaneous;
1981; Roos et al., 1989; Thomas et al., 1990; Palmowski
familial status; and complications of NF1. The follow-up
et al., 1991; Lupski et al., 1993; Hughes, 1994; Ferner et al.,
period was recorded when present.
1996; Créange et al., 1999; Pascual-Castroviejo et al.,
2000). Indeed, apart from peripheral nerve deficits related
to proliferation of MPNSTs, only eight cases of chronic Biological investigations
peroneal muscular atrophy, the so-called neurofibromatous To consider NF1-associated neuropathy, the patients must
neuropathy (Thomas et al., 1990), have been reported (Mur- have normal or negative results for the following investiga-
phy et al., 1980; Thomas et al., 1990; Hughes, 1994) and tions: fasting morning blood glucose level, sedimentation
linked to proliferation of neurofibroma-like tissue (Thomas rate, urea, creatinine, serum protein immunoelectrophoresis
et al., 1990). and quantitative dosage of immunoglobulins, antinuclear anti-
Conversely, peripheral neuropathy in neurofibromatosis 2 bodies, thyroid-stimulating hormone, vitamin B12 and folate
has been shown to be much more frequent, with 66.7% elec- serum levels, human immunodefiency virus (HIV), and hepa-
trophysiological abnormalities and 46.7% clinical abnormal- titis B and C viruses. According to clinical and electrophy-
ities (Sperfeld et al., 2002). Therefore, we have evaluated the siological presentation, a genetic testing for hereditary motor
peripheral nerve involvement in a series of adult patients with and sensory neuropathy type 1 was performed.
NF1 and report the presentation, classification and prognosis
of peripheral neuropathies in a cohort of 18 NF1 patients
assessed by electrophysiological, radiological and some Electrophysiological study
pathological features. This study will enlarge the phenotypic All data from electrophysiological studies were included in
spectrum of previously described NF1-associated peripheral this study. Classification of the neuropathy as axonal or
neuropathies. demyelinating was determined according to the criteria of
 Neurofibromatosis 1 neuropathies 1995

demyelinating neuropathies (Ad Hoc Subcommittee of the the neurofibromas of the neck, the mediastinum and the
American Academy of Neurology AIDS Task Force, 1991). pelvis. He died due to tracheal obstruction related to his
neurofibromas.
Radiological study Patient 2. This 32-year-old man with sporadic NF1 had a 3
month history of increasing gait difficulties that progressively
All patients except two had an MRI study of the spinal cord
affected his walking capacity. At the time of examination, he
and nerve roots. Pelvis–abdominal MRI was performed in 12
was able to walk 100 m with two crutches and had bladder
patients and chest MRI in five. In nine patients, MRI of the

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retention dysfunction. Clinical examination showed a severe
lower limbs was also performed. We evaluated the presence or
motor deficit of the lower limbs, a global sensory deficit at T2,
absence of neurofibromas, and, if present, their location (intra-
lower limb areflexia and a bilateral positive Babinski sign.
dural, foraminal or paraspinal), and distribution (diffuse of
Spinal MRI examination showed numerous paraspinal neuro-
focal) along the nerve or nerve roots was also recorded.
fibromas along the spinal cord (Fig. 2). Pulse intravenous
methylprednisolone induced a transitory improvement in
walking capacity and recovery of lower limb stretch reflexes.
Pathological study However, this improvement was brief, as the patient became
When available in our files, superficial peroneal nerve and paraplegic 6 weeks later.
peroneal frozen muscle biopsy and formalin-fixed samples Patient 3. This 16-year-old male with sporadic NF1 pre-
were examined after staining with haematoxylin and eosin. sented with a peripheral nerve sheath tumour of the right foot
that was treated by chemotherapy (vincristine, ifosfamide,
mesna, actinomycine D, methylprednisolone twice then vin-
Results cristine, ifosfamide, mesna, etoposide once) then 1 month
Patients clinical histories later by an amputation of the limb. After the third course
of chemotherapy, he developed a bilateral foot drop, and
Our series included 18 patients (four women and 14 men) with
several weeks later a progressive weakness of both hands.
diffuse peripheral neuropathy and NF1, of which 16 had clin-
Clinical examination showed a diffuse areflexia, a distal
ical symptoms or signs suggestive of peripheral nerve involve-
weakness and wasting of the four limb muscles, with lower
ment. Prevalence of symptomatic neuropathies in NF1 was
left limb predominance, and a distal sensory impairment of all
estimated at 2.3% in the cohorts of 688 patients selected from
modalities. An MRI study showed multiple tumours of var-
the two NF clinics (1.82% in the Réseau NF-Mondor and
ious sizes in the peripheral nerves (Fig 3A and B). The patient
3.6% in NF-Rhône-Alpin). Mean age 6 SD of the patients
had a slight clinical and electrophysiological improvement
at the time of study was 32.5 6 13.4 years (range 15–62).
after 1 year. Six months later, he had chest surgery for pul-
Eleven of the 18 patients were new mutations based on family
monary metastasis. He died 1 year later of disseminated
history. Other clinical features of NF1 are summarized
metastasis.
in Table 1.
Patient 4. This 42-year-old woman with a history of famil-
Patients were classified according to the absence or pre-
ial NF1 and acute pancreatitis presented with a progressive
sence of symptoms and severity of the peripheral neuropathy.
bilateral four limb weakness and distal paraesthesia for 5
months. Neurological examination showed abolished ankle
reflex, biceps reflex and brachioradialis reflex, bilateral
Group 1. Moderate and severe symptomatic motor deficits in the tibialis anterior and peroneal muscles
neuropathies (patients 1–8) and hand extensor muscles of both hands. There was a stock-
Patient 1. This 20-year-old man with sporadic NF1 had a like sensory deficit of pain, vibration and touch sensations.
previous history of sleep apnoea, tracheal stenosis, hydro- Superficial peroneal nerve biopsy was performed and is
nephrosis related to compressive neurofibromas and a neck described later.
dysmorphy related to subcutaneous neurofibromas. He pro- Patient 5. This 28-year-old man with a history of sporadic
gressively developed a lower limb distal motor deficit from NF1 complained for 3 years of pain in the lateral aspect of the
the age of 16 years. The patient presented with a stepping gait forearms and, more recently, of numbness in the right thumb
related to a symmetric distal motor deficit of the lower limbs and left little finger, a progressive weakness of the left
predominating on the dorsal flexor muscles. Distal pain sen- shoulder and hands, and paraesthesias in both feet. He had
sation and toe position evaluation was slightly decreased. He surgery for a pulmonary artery stenosis at 6 years old, was
had bilateral pes cavus, peroneal atrophy, and ankle and patel- blind in the left eye, and had a palsy of the four lower cranial
lar areflexia. Bladder dysfunction with voiding difficulties nerves (IX–X–XI and XII) of the left side with a Horner sign
was also present. Diffuse large neurofibromas were observed related to a plexiform cervical neurofibroma. Neurological
on nerve roots (Fig. 1). There was no duplication of the examination showed weakness and wasting of the intrinsic
17q11.2 PMP 22 gene. He had a very slow motor deficit hand muscles, weakness consistent with a left C5–C6
progression during the 4 years of follow-up but, at the age radicular distribution with absence of bicipital reflex and
of 24 years, the patient experienced a diffuse enlargement of stylo-radial reflex, and no abnormality in the lower limbs.
Table 1 Neurological, cutaneous and demographic features of patients with NF1-associated neuropathy
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9
1996

Age (years) 20 32 16 42 28 51 62 31 34
Age at onset of 16 32 16 42 25 36 47 31 34
neuropathy (years)
Sex M M M F M M M F F
Family history No No No Yes No No No Yes No
Cutaneous 0 0 0 NA 0 >100 0 2–10 10–100
neurofibromas
Subcutaneous >2 >2 >2 NA >2 >2 >2 >2 >2
A. Drouet et al.

neurofibromas
Peripheral nerve Distal lower Proximal and Distal four limb Distal four limb Weakness of Proximal and Distal Lower left foot Spastic
symptoms and limb symmetric distal lower symmetric symmetric intrinsic hand distal lower limb symmetric four pain and motor tetraparesia
signs, other motor and limb symmetric motor and motor and muscles, of left symmetric limb sciatic deficit
neurological stock-like motor deficits, sensory stock- sensory stock- C5–C6 muscles, motor deficits, sensorimotor
manifestations sensory deficits; T2 sensory like deficits; like deficits and ix, x, xi, xii sensory deficits deficits, distal
peroneal level, lower amyotrophy; left nerve palsies in the legs amyotrophy
atrophy, limb areflexia, diffuse areflexia
pes cavus bilateral
Babinski sign
Severity of the þþþ þþ þþ þþþ þþ þþ –
neuropathy
Electrophysiological Demyelinating Demyelinating Demyelinating Demyelinating Demyelinating Demyelinating Demyelinating Demyelinating Demyelinating
classification neuropathy with neuropathy with neuropathy with neuropathy of neuropathy of in the upper neuropathy of neuropathy of neuropathy
severe axonal moderate axonal severe axonal the four limbs the four limbs limbs with the four limbs the lower limbs
features of features of the features of the severe axonal with moderate and severe left
the four limbs four limbs four limbs features in the axonal changes sciatic
lower limbs neuropathy
Root fo/para at Ce, id/fo/para at Ce, fo/para at Th, Sa NA Diffuse fo/para fo/para at Sa Diffuse fo/para Diffuse fo/para id cervical and
neurofibromas Th, Lu,Sa levels Th, Lu levels levels at Ce, Th, Lu, Sa levels diffuse fo/para
(Fig. 1) (Fig. 2) levels
Peripheral nerve NA NA Plexus, NA Plexus and NA NA Lumbo-sacral NA
location of the intercostal, intercostal plexus and
neurofibromas upper and lower nerves lower limbs
limb peripheral
nerves (Fig. 3A
and B)
NF1 complications Hydronephrosis, Paraplegia Scoliosis, None Left eye Syringomyelia None Voluminous left Partial spinal
sleep apnoea related to meningocoel, blindness, from C1 to S2, sciatic nerve cord
and tracheal neurofibroma MPNST (16 spheno-orbital L5 vertebra MPNST compression
stenosis, related compression of y.o). Death at dysplasia, dysplasia, and (Fig. 4A) with spastic
to neurofibroma lower limb roots 18 y.o. cerebral sacral lyses tetraparesia.
compression. and spinal cord hamartoma, MPNST
Death at 24 y.o cervico-
secondary to mediastinal
tracheal stenosis MPNST
Peripheral neuropathy Chronic Subacute Subacute Chronic Chronic Chronic Chronic Mononeuro- Asymptomatic
classification demyelinating demyelinating demyelinating demyelinating demyelinating demyelinating sensorimotor pathy with demyelinating
polyneuropathy polyradiculo- polyneuropathy polyneuropathy polyneuropathy polyradiculo- demyelinating subclinical polyneuropathy
(with axonal neuropathy (with axonal neuropathy with with moderate demyelinating
features) (cauda equina features) severe axonal axonal changes polyneuropathy
syndrome), changes polyneuropathy
spinal cord
compression

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Table 1 Continued
Patient 10 Patient 11 Patient 12 Patient 13 Patient 14 Patient 15 Patient 16 Patient 17 Patient 18
Age (years) 15 20 43 20 20 48 41 24 38
Age at onset of 15 18 42 19 17 44 38 19 38
neuropathy (years)
Sex M M M M M M M F M
Family history Yes Yes Yes No Yes No No No Yes
Cutaneous 0 10–100 2–10 0 0 >100 10–100 10–100 >100
neurofibromas
Subcutaneous 2 >2 >2 >2 >2 0 0 >2 >2
neurofibromas
Peripheral nerve Pain in thighs Stock-like Painful Painful left S1 Stock-like Pain in the distal Painful Pain in the distal Thoracic 9 level
symptoms and signs, and calves while sensory deficits, dysesthesias in radiculopathy sensory deficits, parts of the dysaesthesias in part of the four paraplegia
other neurological walking diffuse right L4 and decreased four limbs the distal part limbs, right
manifestations enlargement of S1 territories, reflexes in the of the four sciatic pain,
peripheral decrease of lower limbs limbs, decreased pyramidal motor
nerves lower limb ankle reflexes signs of the four
stretch reflexes limbs
Severity of the – þ – – þ – – – –
neuropathy
Electrophysiological Demyelinating Demyelinating Demyelinating Demyelinating Demyelinating Axonal sensory Axonal sensory Axonal Axonal
classification neuropathy of neuropathy of neuropathy of neuropathy of neuropathy of polyneuropathy neuropathy of neuropathy of neuropathy of
the lower limbs the four limbs the lower limbs the four limbs the lower limbs of the four limbs the lower limbs the lower limbs the lower limbs
with mild axonal with mild axonal
features features
Root neurofibromas fo/para at Lu, fo/para at Ce (id fo/para at Ce, Th fo/para at Sa fo/para at Th, None None Diffuse at NA
Sa levels C1–C3), Th, Lu, (id 4,6, 8), Lu, levels Lu, Sa levels fo/para from Ce
Sa levels (Fig. 6) Sa levels. (Fig. 7A and B) to Sa levels, id at
Ce levels
Peripheral nerve Lu, Sa plexus Plexus, Lumbo-sacral Lumbo-sacral Lumbo-sacral NA None Plexus, upper NA
locations of the and lower limbs intercostal, plexus, lower plexus and plexus and and lower limb,
neurofibromas (sciatic nerves) lower and upper limb and lower limb proximal part of and intercostal
(Fig. 5A and B) limb nerves intercostal nerves lower limb nerves
nerves nerves,
intercostal
nerves
NF1 complications None Large C6
Asymptomatic Left paraspinal Asymptomatic None None Right blindness, Spastic
right root
C2-spinal MRI S1 neurofibroma compression of C2 myelopathy paraplegia as a
schwannoma
abnormality surgically vessels and secondary to id complication of
surgically removed pelvis viscera neurofibromas. kyphoscoliosis
removed surgery
Peripheral neuropathy Paucisympto- Chronic sensory Right L4/S1 Left S1 Chronic sensory Chronic sensory Chronic axonal Chronic lower Asymptomatic
classification matic demy- demyelinating radiculopathies radiculoneuro- demyelinating painful axonal sensory limb sensory axonal
elinating polyneuropathy and asympto- pathy and polyneuropathy polyneuropathy polyneuropathy axonal polyneuropathy
polyneuropathy matic asymptomatic with mild axonal polyneuropathy
Neurofibromatosis 1 neuropathies

demyelinating demyelinating features

polyneuropathy polyneuropathy

y.o. = years old; MPNST = malignant peripheral nerve sheath tumour; id = intradural; fo = foraminal; para = paraspinal; Ce = cervical nerve root; Th = thoracic nerve root; Lu = lumbar
nerve root; Sa = sacral nerve root; NA = not available.
1997

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1998 A. Drouet et al.

(distal more than proximal), impaired sensations in the

legs, absence of ankle reflexes and decreased patellar and
upper limb reflexes.
Patient 7. This 62-year-old patient with sporadic NF1 had a
chronic painful right C1 radiculopathy. He had chronic motor
and sensory deficits of the upper and lower limbs that pre-
cluded fine movements of the hands and the capacity to run

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for several years. Neurological examination showed a distal
upper and lower limb areflexia, a symmetric distal motor and
sensory deficit, and a distal amyotrophy of the four limbs.
Patient 8. This 31-year-old woman with familial NF1 was
referred to neurologists because of a left foot pain she had been
experiencing for 6 months. Examination was normal except for
an almost complete plantar extension motor deficit of the left
foot with a sensory deficit in the anterior part of the sole and an
intense pain in the lower part of the left foot. An MRI study
Fig. 1 MRI examination of the chest showing enlargement of the showed large diffuse neurofibromas of the nerve and nerve roots
thoracic roots and diffuse large proximal neurofibromas of the extending from the pelvis to the feet and a voluminous multi-
thoracic nerves (patient 1) (T2-weighted image). Demyelinating lobular tumour of the left thigh (Fig. 4A). FDG PET scanning
sensorimotor polyneuropathy.
showed an intense contrast enhancement of this tumour
(Fig. 4B). Biopsy was consistent with an MPNST.

Group 2. Asymptomatic, paucisymptomatic and

mild neuropathies (patients 9–18): Group 2 A
demyelinating neuropathies (patients 9–14)
Patient 9. This 34-year-old woman with sporadic NF1 devel-
oped a spastic tetraparesia in a 3 month period. This compli-
cation was related to the progression of numerous intradural
benign neurofibromas. She previously had exhibited slowing
nerve conduction velocities by electrophysiological examina-
tion. She had no clinical abnormality suggestive of peripheral
neuropathy. Urgent laminectomy prevented tetraplegia.
Two years later, she developed an MPNST from a plexiform
neurofibroma of the right arm. A limb amputation was
performed.
Fig. 2 Frontal MRI image of the lumbar roots and plexus (patient Patient 10. This 15-year-old male with familial NF1 experi-
2) showing diffuse proximal large neurofibromas (T1-weighted enced pain for several months in the posterior aspects of
image). Demyelinating sensorimotor polyneuropathy. his thighs and calves while walking. Neurological examina-
tion was normal. Symptomatic treatment with amitryptiline
decreased the pain. Electrophysiological examination showed
A [18F]fluoro-2-deoxyglucose (FDG) PET scan showed decreased conduction velocities in the lower limbs. Genetic
enhancement of the left cervical tumour. Surgery with partial testing for PMP 22 gene duplication was negative. MRI showed
removal of this tumour disclosed an MPNST. a diffuse enlargement of lumbar and sacral roots extending into
Patient 6. This 51-year-old man with a history of sporadic the sciatic nerves (Fig. 5A and B). Cervical echography showed
NF1 had painful gait difficulties, chronic left sciatic pain, numerous multiple neurofibromas along the vascular axis.
retentionary hypoactive bladder dysfunction for 15 years Patient 11. This 20-year-old man with familial NF1 had
related to a C2–T12 syringomyelia, lower lumbar vertebra chronic pain of the anterior aspects of both forearms and
and pelvic bone dysplasia, a meningocoel at the left L5 thighs for 2 years. Clinical examination showed a distal
and S1 vertebra, and bilateral pelvic fracture related to osteo- hypaesthesia of all modalities in the feet, decreased ankle
malacia. Two large neurofibromas in the right buttock and reflexes and a diffuse palpable enlargement of peripheral
right thigh were surgically removed 1 year later. In the 2 years nerves. MRI examination showed multiple paraspinal tumour
preceding the examination, he was progressively confined to a masses with bilateral intradural neurofibromas from C1 to C3,
wheelchair because of a progressive hypotonic peripheral and a spinal cord hyperintense signal on T2-weighed images
paraplegia. On examination, there was a diffuse weakness at the C2 level (Fig. 6).
 Neurofibromatosis 1 neuropathies 1999

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Fig. 3 Sagittal image in T2 fat saturation: hyperintense multinodular enlargement of the left radial (A) and femoral and sciatic nerves (B) of
patient 3. The multiple neurofibromas are visible all along the nerves. Demyelinating sensorimotor polyneuropathy.

Fig. 4 (A) Bilateral sagittal images of the thighs showing diffuse proliferation of neurofibromas in the right sciatic nerve and a voluminous
deformation of the left sciatic nerve related to the development of an MPNST in a patient with a left sciatic nerve deficit and a
demyelinating polyneuropathy. (B) The FDG PET scanning showed a intense contrast enhancement consistent with the left sciatic nerve
malignant tumour. Demyelinating neuropathy with sciatic nerve deficit.

Patient 12. This 43-year-old man with familial NF1 had a had increased right cervical pain, whereas clinical examina-
right C6 root schwannoma and had experienced painful dys- tion was unchanged and an FDG PET scan was normal.
esthesia in the right L4 and S1 territory for several months. Patient 13. This 20-year-old man with sporadic NF1 had a
Neurological examination was normal, except for a decrease chronic painful left S1 radiculopathy for 18 months related to
of right bicipital and lower limb reflexes. Two years later, he an extradural neurofibroma. Surgery of this neurofibroma
2000 A. Drouet et al.

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Fig. 5 MRI sagittal (A) and axial (B) sections of the thigh of patient 10 in T2 fat saturation sequences showing hyperintense multiple bulky
tumours along the right sciatic, common peroneal and tibial nerves without vessel compression. Asymptomatic demyelinating neuropathy.

6 month later showed a demyelinating polyneuropathy in

the lower limbs.

Group 2B: axonal neuropathies (patients 15–18)

Patient 15. This 48-year-old man with sporadic NF1
presented with chronic pain of the distal parts of
the four limbs. Clinical examination was normal, including
stretch reflexes.
Patient 16. This 41-year-old man with sporadic NF1 has a
history of carpal tunnel syndrome, urethral stenosis, and
hypertrophic cardiopathy with junctional tachycardia. For 3
years he has experienced painful dysaesthesia in the distal
part of the four limbs. Neurological examination showed
decreased ankle reflexes. Spinal cord and limb MRI were
normal.
Patient 17. A 24-year-old woman with sporadic NF1 had
Fig. 6 Hyperintense bilateral intra-axial and foraminal tumour
masses at the C2 level with right spinal cord hyperintense signal chronic pain for the past 5 years in the proximal and distal
(cervical axial image in T2 fat saturation sequence). Mild sensory parts of the four limbs, particularly in the right L5 territory,
demyelinating polyneuropathy. and spastic lower limbs. She had surgery 3 years prior to
examination for a C1–C2 spinal cord compression related
partially decreased the pain. Neurological examination was to bilateral intradural neurofibromas. Neurological examina-
normal. No change occurred during the following 6 month tion showed a moderate spasticity of the lower limbs, diffuse
period. hyper-reflexia and bilateral Babinski sign without sensory
Patient 14. This 20-year-old man with familial NF1 com- abnormalities.
plained for 3 years of distal and proximal burning pain in the Patient 18. A 38-year-old man with a history of familial
lower limbs. Neurological examination showed decreased NF1 with numerous cutaneous and subcutaneous neurofibro-
stretch reflexes in the lower limbs and altered sensory exam- mas was referred to the NF clinic for follow-up. He had a past
ination in the feet and legs. MRI showed numerous neuro- history of severe kyphoscoliosis that required surgical correc-
fibromas of lumbosacral roots and nerves (Fig. 7A and B). tion at the age of 30 years. Unfortunately, it was followed by
While neurological symptoms and examination were complete paraplegia at the T9 thoracic level. Treatment of
unchanged, electrophysiological examination 2 years and the pyramidal syndrome-associated spasticity required an
 Neurofibromatosis 1 neuropathies 2001

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Fig. 7 (A) Large proximal neurofibromas in patient 14 visible as hyperintense tumour masses of roots and lumbosacral plexus which
pressed back vessels and internal organs (bladder) (pelvic coronal image in T2 fat sat image). (B) The same patient with proximal thoracic
nerves enlarged by neurofibromas (T2 fat saturation image of thoracic coronal section). Mild sensory demyelinating polyneuropathy.

intrathecal baclofen pump. A systematic electrophysiological foramina. Three patients had neurofibromas in the lumbar
examination showed an axonal polyneuropathy. and sacral roots only. Eight patients had intradural neuro-
fibromas. Of these eight patients, five had a spinal cord com-
Investigations pression with clinical (n = 3) or radiological changes (n = 2).
Biological investigations Eight out of nine patients had peripheral nerve multinodular
There was no remarkable biological abnormality in this series images consistent with diffuse neurofibromas of the nerves.
of patients, including negative genetic testing for hereditary Neurofibromas along peripheral nerves appeared as multiple
motor and sensory polyneuropathy type 1 in patients 1 and 10. tumour masses with high signal intensity in T2-weighted
images and T2 fat saturation images (all patients), with nor-
mal or more often low signal intensity in T1-weighted images
(Figs 2, 3A and B, and 4A). Five out of seven patients had a
Electrophysiological study slight contrast enhancement of some neurofibromas. Seven
Electrophysiological data are reported in Table 2. All patients out of eight patients, in whom a complete MRI study was
had a diffuse symmetric polyneuropathy (even if some had performed, had diffuse neurofibromas in the roots, plexus,
superimposed asymmetric changes). The neuropathy involved nerves trunks and nerves endings in muscles and subcuta-
the four limbs (10 out of 17 patients) or the lower limbs only neous tissue.
(seven out of 17 patients). Four patients had an axonal poly-
neuropathy, and 14 had a neuropathy consistent with either
pure demyelinating abnormalities (in seven cases) or asso-
ciated with axonal changes (in seven cases). Electrophysio- Pathological study
logical changes were consistent with severe (patients 1, 3 and In one patient (patient 4), nerve and muscle biopsy was per-
6), moderate (patients 2, 7, 11 and 14) or light (patients 5, 8, formed and showed the presence of typical neurofibromas. In
10, 12, 13, 15, 16, 17 and 18) axonal or demyelinating nerve cross-sections, they appeared in individual fascicles as
abnormalities. Severe changes were associated with severe target-like formations consisting of a central area of compact
or moderate clinical symptoms (patients 1, 3 and 6), while endoneurial tissue, a ring of loose tissue with myxoid appear-
moderate or light electrophysiological abnormalities were not ance containing sparse collagen bundles, and a peripheral
associated with a severe clinical neuropathy. zone of less altered endoneurial tissue containing myelinated
fibres and moderate Schwann cell proliferation without onion
bulb formation (Fig. 8B). The number of myelinated fibres
Radiological study was decreased throughout the fascicles, and myelin sheaths
Patients underwent a radiological investigation of the spine were completely absent in the central zones of the neuro-
(n = 16), the pelvis (n = 12), chest (n = 5) or limb girdles (n = fibroma (Fig. 8A and B). In the muscle, neurofibromas
9). Fourteen out of 16 patients had diffuse (or multifocal) appeared as focal areas of endomysial connective tissue swel-
paraspinal neurofibromas with expansion to intervertebral ling with a myxoid appearance, smothering muscle fibres.
2002 A. Drouet et al.

Table 2 Electrophysiological data of patients with NF1-associated neuropathies

Group 1

Patient 1 Patient 2 Patient 3* Patient 5 Patient 6 Patient 7 Patient 8

Right Left Right Left Right Left Right Left Right Left Right Left Right Left

Motor nerve conduction

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Median nerve
Amplitude-thenar (mV) >4 7 14 13 18 2.0/5.8 2.2/4.2 1.4 9.8 8.1 12.4 14 12 – 14
Distal latency (ms) <4.2 4.4 4 2.9 3.2 4.9/4.1 4.4/3.5 5.6 4.5 3.2 3.6 4 4 – 3.5
Conduction velocity-forearm (m/s) >47 25 34 43 44 39/40 32/37 33 43 43 43 47 48 – 47
F wave latency (ms) <32 59.4 57 37.6 34 38.2/37.2 0/35.7 48.9 32.9 31.5 32.0 34.5 33.7 – –
Ulnar nerve
Amplitude-hypothenar (mV) >5 7 6 3.8/5.4 2.7/4.5 3.3 7.2 3.1 – 9 9 – 9
Distal latency (ms) <3.7 3.8 4.3 – – 4.0/3.4 4.0/3.5 3.9 3.4 6.8 – 2.3 2.8 – 2.6
Conduction velocity-forearm (m/s) >47 37 40 – – 30/33 32/37 40 40 43 – 46 45 – 48
F wave latency (ms) <34 55.4 55.5 – 40.4/38 36.2/38.3 40.0 36.9 31.1 – 37.7 37.7 –
Radial nerve
Amplitude-forearm (mV) >3 – – – – – – – – – – – – –
Conduction velocity-elbow (m/s) >47 – – – – – – 65 57 – – – – – –
Common peroneal
Amplitude-foot (mV) >2 0 0 1.7 4.2
/
0/0 4.8 2.9 0 0 0.1 0.2 4 3
Distal latency (ms) <6.0 0 0 4.7 4.4
/
0/0 6.1 7.4 0 0 4.7 4.5 3.8 4.1
Conduction velocity-leg (m/s) >40 0 0 30 34
/
0/0 35 35 0 0 33 37 34 31
F wave latency (ms) <56 0 0 0 0
/
0/0 62.4 68.5 0 0 – – – –
Tibial nerve
Amplitude-foot (mV) >3 4.5 5 3.7 2.4
/
0.2/0.2 5.3 10.5 0 0.1 0.3 0.7 7 0.3
Distal latency (ms) <6.5 6 3.6 5.5 4.7
/
10.4/10.6 8.2 8.0 0 8.7 5.3 4.7 3.2 5.6
Conduction nerve velocity-leg (m/s) >40 27 18 31 32
/
26/34 35 36 0 29 35 36 –
F wave latency (ms) <57 54.4 58.7 68.3 70
/
0/0 61.6 60.3 0 0 – 157 –
Sensory nerve conduction
Median nerve
Amplitude (mV)>12 4 20 28 31 3.4/3.2 4.6/9.1 14.7 8.2 10.9 29.5 23 23 – 37
Conduction velocity-wrist (m/s) >42 32 37 61 58 45/47 40/50 38 37 42 35 48 50 – 51
Ulnar nerve
Amplitude (mV) >9 3 4 – –
/3.3
/1.7 3.7 13.3 14.1 14.6 0 0 – 18
Conduction velocity-wrist (m/s) >42 32 40 – –
/44
/45 38 41 33 36 0 0 – 50
Radial nerve
Amplitude (mV) >15 – – – –
/6.2
/0 – 13.7 31.4 – – – – –
Conduction velocity-forearm >40 – – – –
/52
/0 – 33 50 – – – – –
Superficial peroneal nerve
Amplitude (mV) >8 – – 0 0
/
0/0 0 2.4 0 0 0 0 – 0
Conduction velocity-ankle (m/s) >40 – – 0 0
/
0/0 0 31 0 0 – – 0
Sural nerve
Amplitude (mV) >10 0 0 2 4
/
0/0 33.3 17.3 0 0 3 3 10 3
Conduction velocity-ankle (m/s) >40 0 0 36 33
/
0/0 37 36 0 0 33 37 34 32
Electromyogram
Ttibialis anterior/extensor digitorum brevis pedis
Spontaneous activity No No No No Yes No No No No No
Neurogenic volontary contraction Yes Yes Yes Yes Yes Yes Yes Yes Yes No
Group 2A Group 2B

Patient 10 Patient 11 Patient 12 Patient 13 Patient 14 Patient 15 Patient 16 Patient 17 Patient 18

Right Left Right Left Right Left Right Left Right Left Right Left Right Left Right Left Right Left

Motor nerve conduction

Median nerve
Amplitude-thenar (mV) >4 5.9 – 7.0 6.0 – – 10.9 – 5.2 4.1 17 14 8.1 5.8 10.5 9.3 13 19
Distal latency (ms) <4.2 3.2 – 2.9 3.3 – – 3.3 – 2.9 2.9 3.3 3.6 4.3 4.6 3.2 3.2 2.9 2.8
Conduction >47 47 – 40 40 – – 42 – 57 59 56 57 56 61 47 50 54 50
velocity-forearm (m/s)
F wave latency (ms) <32 – – 33.0 36.1 – – 33.0 – 29.5 28.4 – – 27.4 30.2 28.9 27.3 26.8 27.1
Ulnar nerve
Amplitude >5 – – 8.8 10.4 – – 12.3 11.9 2.6 3.3 20 18 7.9 6.6 6.9 6.6 12 11
hypothenar (mV)
 Neurofibromatosis 1 neuropathies 2003

Table 2 Continued
Group 2A Group 2B

Patient 10 Patient 11 Patient 12 Patient 13 Patient 14 Patient 15 Patient 16 Patient 17 Patient 18

Right Left Right Left Right Left Right Left Right Left Right Left Right Left Right Left Right Left

Distal latency (ms) <3.7 – – 2.5 3.0 – – 3.0 3.6 2.5 2.5 2.5 2.9 2.5 2.5 3.3 2.8 2.5 2.7

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Conduction >47 – – 39 39 – – 46 45 52 46 57 57 60 54 53 51 52 56
velocity-forearm (m/s)
F wave latency (ms) <34 – – 41.2 38.5 – – 35.9 35.2 31.5 35.1 30 30 28.3 29.3 31.3 30.4 29.3 29.1
Radial nerve
Amplitude-forearm (mV) >3 – – – – – – 3.8 – – – – – – – 3.1 3.3 –
Conduction >47 – – 47 – – – 49 – – – – – – – 53 57 –
velocity-elbow (m/s)
Common peroneal
Amplitude-foot (mV) >2 4.5 4.4 0.4 0.7 3.7 4.0 3.1 3.1 2.0 0.2 – – 3.8 3.6 1.1 1.0 1.7 0.6
Distal latency (ms) <6.0 5.7 5.2 4.9 7.7 6.2 5.5 4.7 5.2 5.4 13.6 – – 4.1 3.7 4.3 5.0 3.2 2.9
Conduction >40 30 32 28 28 39 43 37 38 37 24 – – 51 47 41 37 40 40
velocity-leg (m/s)
F wave latency (ms) <56 59.1 67.8 – – 65.1 57.8 59.2 60.4 59.0 0 – – 44.2 49.0 53.4 56.8 – –
Tibial nerve
Amplitude-foot (mV) >3 10.5 6.7 2.5 3.8 2.5 2.0 7.3 7.4 1.9 0.7 – – 4.0 3.8 5.4 3.7 1.8 3.7
Distal latency (ms) <6.5 5.7 6.9 9.3 7.8 7.1 7.6 6.9 6.0 10.5 12.8 – – 5.3 5.3 5.9 6.2 3.6 2.9
Conduction nerve >40 31 33 27 30 35 33 36 36 30 34 – – 44 47 39 40 42 41
velocity-leg (m/s)
F wave latency (ms) <57 63.3 59.5 68.4 77.9 68.3 71.9 66.4 64.6 62.5 0 – – 49.3 49.2 50 51.1 51.3 51.5
Sensory nerve conduction
Median nerve
Amplitude (mV) >12 – – 12.8 25.6 – – 31.9 – 30.4 16.8 24 16.6 4.0 14.1 16.0 13.9 35 26
Conduction >42 – – 55 59 – – 54 – 55 59 54 57 46 40 55 52 70 72
velocity-wrist (m/s)
Ulnar nerve
Amplitude (mV) >9 – – 7.5 7.6 – – 18.3 15.9 – – 19 22 6.7 6.8 8.8 8.8 16.5 16.5
Conduction >42 – – 55 56 – – 48 44 – – 57 54 43 47 47 46 60 63
velocity-wrist (m/s)
Radial nerve
Aplitude (mV) >15 – – 20.3 13.1 – – 20.1 – – – – – 32.8 40.7 12.3 17.6 52 –
Conduction > 40 – – 54 48 – – 59 – – – – – 62 59 56 53 62 –
velocity-forearm
Superficial peroneal nerve
Amplitude (mV) >8 9.3 13.3 0 0.8 3.0 2.0 4.8 3.1 2.2 0 9.0 4.5 2.9 1.5 4.9 3.3 0 0
Conduction >40 33 34 0 21 38 30 37 39 21 0 39 42 34 36 37 38 0 0
velocity-ankle (m/s)
Sural nerve
Amplitude (mV) >10 4.9 3.9 1.1 7.0 2.2 1.7 9.6 14.4 3.2 1.2 6.5 5.5 8.4 7.6 0.8 1.1 – –
Conduction >40 32 31 32 33 37 37 40 46 25 16 47 50 45 39 20 33 – –
velocity-ankle (m/s)
Electromyogram
Tibialis anterior/extensor digitorum brevis pedis
Spontaneous activity No No No No No No No No No No No No
Neurogenic volontary Yes No Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes NA NA
contraction

*First/second examination. NA = not able to perform.

Muscle neurofibromas were probably developed from nerve (–), with mono- or multiple sensory radiculopathy (patients
twigs. Their borders were ill defined, as commonly observed 10, 12, 13 and 17). Patients 11 and 14 had a mild sensory
in cutaneous neurofibromas (Fig. 8C and D). polyneuropathy (þ). Five patients (patients 1, 4, 5, 7 and 8)
had moderate motor and sensory neuropathy (þþ); patient 8
had a moderate mononeuropathy with an asymptomatic poly-
Clinical and investigation synthesis neuropathy. Three patients (patients 2, 3 and 6) had a severe
Eight patients had an asymptomatic (patients 9, 12, 13 and 18) motor and sensory polyneuropathy (þþþ). Patients 2, 5 and 6
or paucisymptomatic (patients 10, 15, 16 and 17) neuropathy had an associated polyradiculopathy. While patients 2 and 3
2004 A. Drouet et al.

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Fig. 8 (A and B) Cross-sections of the nerve biopsy of patient 4 (A 25; B 100). (A) The neurofibromatous tissue appears in the
nerve fascicle as a central area of compact tissue, surrounded by loose tissue with myxoid appearance containing sparse collagen bundles,
and a peripheral zone of less altered endoneurial tissue. (B) The myxoid zone (asterisk) contains virtually no cells, whereas the
peripheral zone still contains a number of visible myelinated fibres and shows no onion bulb formation (arrows). (C and D) Muscle biopsy
in patient 4 (  40): presence of neurofibromas consisting of endomysial connective tissue swelling with a myxoid appearance as
commonly observed in cutaneous neurofibromas.

had a peripheral neuropathy with a subacute course, the others Morbidity of patients
had chronic manifestations. Patients 2, 9, 17 and 18 also had Ten out of 18 patients had a poor prognosis related either to
spinal manifestations. the neuropathy (patients 2, 3 and 6) or to NF1 complications
(patients 1, 2, 3, 5, 6, 8, 9, 11, 17 and 18). Four out of 18 (22%)
Severity of the neuropathy developed an MPNST, a much higher proportion than what
There was no relationship between the severity of the neuro- is observed in the whole population of NF1 (x2 = 8.57;
pathy to age, sex, family status, presence or absence of sub- P < 0.004).
cutaneous neurofibromas, presence of diffuse large Severe NF1 morbidity and mortality were not related to age
neurofibromas or electrophysiological features. However, at the time of neuropathy diagnosis, or duration of neuropathic
severe neuropathies (þþ and þþþ) were more frequently symptoms, presence of subcutaneous neurofibromas, family
associated with severe complications of NF1, and axonal NF1 history and gender. However, severe complications
neuropathies were never associated with severe neuropathies of NF1 were more usually observed in patients with severe
(Tables 1 and 3). neuropathies (þþ and þþþ) (Table 3).
Patients with demyelinating neuropathies with or without In this study, 15 out of 17 patients had subcutaneous neu-
axonal changes did not have a higher risk of severe complica- rofibromas, a higher proportion than in the global population
tion (either MPNST or organ compression) than patients with of patients with NF1 in the Réseau NF-Mondor (x2 = 16.856;
axonal neuropathies. However, the proportion of severe com- P < 0.0001). In addition, 14 out of 16 had proximal neuro-
plications of NF1 for patients with demyelinating neuro- fibromas, a higher proportion than is estimated in patients with
pathies with severe axonal changes was 100%, whereas for NF1 (82 versus 36–57% of patients, P < 0.03) (Egelhoff et al.,
patients with demyelinating neuropathies with moderate 1992; Poyhonen et al., 1997; Tonsgard et al., 1998).
axonal changes, pure demyelinating neuropathies and pure Patients with proximal paraspinal neurofibromas did not
axonal neuropathies, the proportion was 50%. Axonal and have a higher risk of severe complications, i.e. organ com-
demyelinating neuropathies were associated with an equiva- pression or MPNST (eight out of 14 patients), than patients
lent delay of neuropathic symptom evolution, of 3 6 2.1 and without proximal neurofibromas (none out of two) (Fisher’s
3.4 6 1 years, respectively. exact test P > 0.05). However, all patients with severe
 Neurofibromatosis 1 neuropathies 2005

Table 3 NF1 features and complications (i.e. organ/spinal cord compression or MPNST) according to the severity
of the neuropathy
Moderate and Asymptomatic, paucisymptomatic P
severe neuropathies and mild neuropathies
Patients (number) 1–8 9–18 NS
Age (years) 35.25 6 15.6 30.3 6 11.8 NS
Delay of evolution (years) 5 6 5.6 3.2 6 2.3 NS

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Sex (M : F) 6:2 8:2 NS
Family history 4/9 (44.4) 2/9 (22.2) NS
Subcutaneous neurofibromas (two or more) 8/8 (100%) 8/10 (80%) NS
Severe complication 6/8 (75%) 3/10 (30%) NS
Axonal features only 0/7 (0%) 4/10 (40%) NS
Demyelinating features 7/7 (100%) 6/10 (60%) NS
Pure 2/7 4/10
With axonal features 5/7 2/10
Diffuse proximal neurofibromas 7/7 (100%) 7/9 (78%) NS

complications had proximal neurofibromas. Diffuse proximal Palmowski et al., 1991; Lupski et al., 1993 (two patients);
large neurofibromas were not associated with severe neuro- Hughes, 1994; Ferner et al., 1996; Pascual-Castroviejo et al.,
pathies or with demyelinating or axonal electrophysiological 2000]. In other cases reported as NF1-associated neuro-
changes. pathies, association with CMT1a (Lupski et al., 1993) or
other types of neurofibromatoses (possible NF1 but absence
of all required criteria for the patient of Béquet et al., 1990;
NF2 for patient 3 of Thomas et al., 1990) cast some doubt on
Discussion the conclusions that can be reached regarding these patients.
The peripheral neuropathies observed in this study of 18 Paradoxally, the literature is much more detailed on neuro-
patients enlarge the spectrum of the so-called neurofibroma- pathies associated with NF2, a rarer condition, where 24
tous neuropathy (Thomas et al., 1990), including patients with patients have been reported [Onishi and Nada, 1972; Thomas
asymptomatic polyneuropathy, mildly symptomatic sensory et al., 1990 (patient 3); Kilpatrick et al., 1992; Overweg-
polyneuropathy, slowly progressive sensorimotor polyneuro- Plandsoen et al., 1996; Iwata et al., 1998; Gijtenbeek et al.,
pathy and severe subacute motor predominant polyradiculo- 2001; Hagel et al., 2002; Sperfeld et al., 2002]. The term
neuropathy. Moreover, superimposed radicular changes neurofibromatous neuropathy was first used to describe two
frequently were associated with the polyneuropathies. Elec- patients who had a slowly progressive symmetric distal motor
trophysiological investigations disclosed various patterns of and sensory neuropathy with late childhood onset, and char-
abnormalities from mild sensory axonal polyneuropathy to acterized by distal muscle atrophy and pes cavus. These two
diffuse subacute motor and sensory demyelinating polyra- patients had reduced motor conduction velocities (Thomas
diculoneuropathy with axonal changes. et al., 1990). Neurofibromatous neuropathy was considered
Ten out of 18 patients had a poor prognosis either related to as a relatively benign condition with a slowly progressive
the neuropathy itself or to an associated life-threatening com- course characterized by a modest disability. Indeed, eight
plication of NF1, such as spinal cord compression by intra- patients in the present series of 18 had an asymptomatic or
dural neurofibromas or MPNSTs. These complications were paucisymptomatic neuropathy, and two had a mild sensory
observed specifically in patients with a demyelinating neuro- neuropathy. Strikingly, only eight of 13 patients with NF1-
pathy with severe axonal changes. A unique pattern of large associated neuropathy in the literature (Table 4) had the typi-
tortuous nerves related to the proliferation of neurofibromas cal presentation of the chronic sensorimotor neuropathy with
along nerve trunks was disclosed by MRI investigation of distal muscular atrophy (seven patients) and pes cavus (three
nerves in some patients with peripheral neuropathies, parti- patients) [Thomas and Eames, 1971; Bradley et al., 1974;
cularly in those with demyelinating features. Finally, the Murphy et al., 1980; Bosch et al., 1981 (patients 1, 2 and
large majority of patients with peripheral neuropathies and 4); Thomas, 1990; Hughes, 1994]. However, one patient had a
NF1 had diffuse proximal neurofibromas and subcutaneous chronic motor neuropathy (patient 3 of Bosch et al., 1981) and
neurofibromas. three had a pure sensory neuropathy (Palmowski et al., 1991;
Surprisingly, despite its relevance to the clinical spectrum Ferner et al., 1996; Pascual-Castroviejo et al., 2000). In these
of NF1, there have been no previous publications addressing patients, five had a diffuse enlargement of peripheral nerves.
the question of peripheral neuropathies in NF1, except as case In the present study, three patients experienced severe and
reports [Thomas and Eames, 1971; Bradley et al., 1974 four moderate peripheral nerve sensorimotor deficits, while
(patient 1); Bosch et al., 1981 (patients 1–4); Roos et al., two patients had a subacute course and three patients had an
1989; Béquet et al., 1990; Thomas et al., 1990 (patient 2); associated poly- or multifocal radiculopathy that does not
 2006

Table 4 Neurological, cutaneous and demographic features of NF1-associated neuropathy in the literature
Lambers (1952) Thomas and Eames Bradley et al. Bosch et al. (1981) Bosch et al. (1981) Bosch et al. (1981) Bosch et al. (1981)
(1971) (1974) case 1 case 1 case 2 case 3 case 4
Age (years) NS 38 58 32 57 29 21
Age at onset of NS 20 19 8 NA NA 19
A. Drouet et al.

neuropathy (years)
Sex NS M F M F F M
Family history NS 1 brother? Yes Yes Yes Yes No
Cutaneous NS No Yes No Yes Yes No
neurofibromas
Subcutaneous NS Yes yes yes NS NS yes
neurofibromas
Peripheral nerve NS Chronic distal Chronic distal Chronic distal Chronic distal Distal lower limb Chronic distal
symptoms and symmetric symmetric symmetric symmetric motor motor neuropathy symmetric
signs, other sensorimotor and sensorimotor sensorimotor predominant with amyotrophy sensorimotor
neurological progressive PN of progressive PN of progressive PN of progressive PN of progressive PN of
manifestations the four limbs. the four limbs. the four limbs. the four limbs. the lower limbs.
Amyotrophy Amyotrophy. Thick Severe amyotrophy Amyotrophy and Amyotrophy
ulnar nerves and PC. Walking PC. Tandem gait
impaired at 26 years
old
Electrophysio- NS Lower limb Axonal neuropathy Slow nerve Slow nerve NS Slow nerve
logical denervation. conduction conduction conduction
classification Reduced nerve velocities in the velocities in the velocities in the
conduction median nerve median nerve median nerve
velocities in the (–40%) (–20%) (–20%)
upper limbs
Roots NS NS. EN Multiple id at Ce No NS NS Normal cervical
neurofibromas and upper Th myelography
levels; normal CSF
Nerve biopsy Diffuse thickening; Compact Endoneurial Loss of myelinated Similar to NS NS
findings degeneration of endoneurial tissue proliferation of fibres. Onion bulbs; preceding Bosch
nerve fibres; with loss of linear Schwann increased case with more
mucoid interstitial myelinated fibres; cells. Loss of endoneurial onion bulbs and
material neurofibromatosis myelinated nerve connective tissue. clusters of
tissue fibres Clusters of regenerating
regenerating myelinated nerve
myelinated nerve fibres
fibres
Complications of NS no Deafness, mutism, Congenital Deafness in Generalized Mild thoracic
NF1 partial albinism, iris deafness and adolescence seizures (onset at 21 scoliosis
abnormalities mutism at 5 years (normal cerebral years old)
old (normal CT scan)
cerebral CT scan)

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 Roos et al. Thomas et al. Palmowski et al. Hughes (1994) Ferner et al. Pascual-
(1989) (1990) case 2 (1991) (1996) Castroviejo et al.
(2000)
Age (years) 30 32 24 27 47 15
Age at onset of the 25 15 23 25 42 14
neuropathy (years)
Sex M M F M M F
Family history No Yes No NS NS No
Cutaneous No Yes No NS NS No
neurofibromas
Subcutaneous Yes Yes Yes NS NS Yes
neurofibromas
Peripheral nerve Chronic distal Chronic distal Chronic distal Subacute/ Chronic distal Chronic pain in
symptoms and signs, symmetric symmetric paraesthesias in chronic sensory PN of nerve trunk
other neurological sensorimotor sensorimotor the hands and progressive the four limbs territories with
manifestations progressive PN progressive PN feet. Multifocal sensori-motor painful irregular
predominating predominating sensory painful PN with EN. Diffuse
in the lower in the lower nodes. Normal peroneal areflexia
limbs. limbs. neurological atrophy
Amyotrophy Amyotrophy examination
EN, PC except painful EN
Electrophysiological Slow nerve Reduced nerve Reduced nerve Axonal Predominantly Reduced motor
classification conduction conduction conduction polyneuropathy sensory axonal conduction
velocity in tibial velocities in velocities of the lower neuropathy velocities of the
nerve. Absence upper limbs. limbs lower limbs.
of sensory Absence of Absence of
potentials in the sensory sensory
lower limbs potentials in the potentials
upper limbs
Roots neurofibromas fo L3 to S1, id NA NS Yes NS fo Ce to Sa,
L4–L5, brachial intercostals
and lumbo- nerves and limbs
sacral plexus,
femoral and
sciatic nerves
Nerve biopsy Bilateral Similar to the Myelinated fibre NS Multifocal NS
findings plexiform case of Thomas loss, nerve neuro-
neurofibromas and Eames sprouting, fibrous fibromatous
of the Lu-Sa (1971) tissue tissue and
nerves roots variable
reduction in
myelinated
nerve fibre
density
Complications of Asymptomatic No No Enlargement of No Enlargement of
NF1 compression by neurofibromas the left optic
neurofibromas at 34. Death at nerve
of bladder and 35 years old
Neurofibromatosis 1 neuropathies

colon from malignant

peripheral nerve
sheath tumour
2007

EN = diffuse enlargement of peripheral nerve; PN = polyneuropathy; PC = pes cavus; NS = not stated; id = intradural; fo = intraforaminal; Ce = cervical nerve root; Th = thoracic nerve
root; Lu = lumbar nerve root; Sa = sacral nerve root.

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2008 A. Drouet et al.

fit with the relatively benign condition of neurofibromatous Nerve biopsy findings in NF1, reported in the literature,
neuropathy. In the present study and even more strikingly in show various features including macroscopic extensive nodu-
the literature, the duration of the neuropathy was longer in lar thickened nerves (five out of eight patients), neurofibro-
cases of moderate/severe neuropathy than in cases of mild matous tissue (five), loss of myelinated fibres (seven) and
neuropathy, with 4.3 6 5.4 versus 3.2 6 2.3 years and 15.29 even onion bulb formations (two). Giant neurofibromas at
versus 2.33 years, respectively. Large proximal nerves related the root level (Figs 6 and 7A), multiple neurofibromas
to the proliferation of proximal neurofibromas seem to con- along the nerve (Figs 3A and B, 4A, and 5A and B) and

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stitute a key feature of the majority of patients with NF1- intraneural proliferation of neurofibroma-like tissue distally
associated neuropathy. Although proximal nerve hypertrophy (Fig. 8A) may produce compression along roots and nerves.
can be encountered in patients with Charcot–Marie–Tooth This phenomenon may induce axonal degeneration and multi-
disease (Rosen et al., 1989), Déjerine–Sottas disease (Masuda focal myelin sheath loss along the nerve (Fig. 8B) that may
et al., 1992), Noonan syndrome [a genetic disorder that shares explain the varied combination of compound muscle action
features with NF1 (Silburn et al., 1998)], chronic inflamma- potential amplitude decrease and slow motor nerve conduc-
tory demyelinating polyradiculoneuropathy (Aı̈di et al., 2002) tion velocities on electrophysiological examination. More-
and NF2-associated neuropathy (Sperfeld et al., 2002), the over, associated factors, such as chemotherapy in patient
voluminous deformity of nerves with potential organ com- 3 or inflammatory changes in patients with demyelinating
pression related to these proliferations is unique for NF1. In neuropathies, may disclose or increase the severity of an
the present study, 14 out 16 (87.5%) patients with a peripheral asymptomatic neuropathy. In another way, a random associa-
neuropathy had focal or diffuse paraspinal neurofibromas. tion with a CMT1a neuropathy—a genetic location on the
Diffuse proximal neurofibromas affecting all spinal roots mirror segment of chromosome 17—as in two patients in
has been considered exceptional and a distinct entity of the literature (Lupski et al., 1993), could account for some
NF1 (Poyhonen et al., 1997). However, 36–57% of patients cases of demyelinating neuropathies. Other unknown local
with NF1 have spinal neurofibromas (Egelhoff et al., 1992; toxic or metabolic factors, as in NF2 (Sperfeld et al.,
Poyhonen et al., 1997; Thakkar et al., 1999), and 40% of 2002), could also be hypothesized in NF1. Finally, the pre-
patients with spinal neurofibromas are asymptomatic (Thak- sence of one or several specific factors stimulating abnormal
kar et al., 1999). Moreover, whether this condition is asso- Schwann cell development inducing myelin changes, giant
ciated with asymptomatic peripheral nerve involvement has neurofibromas and favouring MPNST onset may account for
not been investigated systematically in these patients. the association observed in the present study. A circulating
Whether these conditions share common genetic determinants factor may well facilitate the development of neurofibromas
remains to be studied. in the nerve roots, where the blood–nerve barrier is weaker.
Ten out of 18 patients had a severe prognosis (morbidity Finally, the presence of subcutaneous neurofibromas in
and mortality) related to the development of MPNST (four patients with NF1-associated neuropathy suggests that
patients, one death), spinal cord (five patients) or organ com- development of giant proximal neurofibromas, peripheral
pressions (two patients, one death) or to the neuropathy itself nerve changes and subcutaneous neurofibromas may
(three patients). This represents a higher proportion than in a be included in a phenotype of deep neurofibromas that may
population of patients with NF1 (Huson et al., 1988; Riccardi, be related to specific genetic alterations that may lead to the
1992; Créange et al., 1999) especially for MPNST (22% in development of MPNST.
this series). It appears that NF1-associated neuropathy is a rare condi-
Interestingly, there is an association between peripheral tion when polyneuropathy is symptomatic. The prevalence of
neuropathy and subcutaneous neurofibromas, which have paucisymptomatic and asymptomatic forms could be more
been shown to be an independent life prognosis factor in frequent. It is not a benign condition that can be characterized
patients with NF1 (Khosrotehrani et al., 2003), highlighting in some cases by an acute or subacute course, and is associated
the potentially poor prognosis of patients with NF1-associated with a high prevalence of life-threatening complications. Peri-
neuropathy and subcutaneous neurofibromas. pheral neuropathy should be screened for in patients with
The axonal features of the so-called neurofibromatous NF1, particularly those with subcutaneous neurofibromas.
neuropathy are not consistent with several patients reported Demyelinating features with progressive appearance of axo-
in this study. Indeed, the majority of patients with a bad nal features should alert one to the potential development of
prognosis had demyelinating electrophysiological features, MPNST or organ compression, and mandate a clinical or
whereas only half of the patients with axonal features had radiological follow-up. Whether systematic electrophysiolo-
life-threatening complications. Moreover, patients with pure gical investigations are required to evaluate the potential risk
demyelinating changes had fewer complications than patients of MPNST remains to be investigated.
with demyelinating neuropathies and severe axonal features.
Does axonal changes constitute a late stage of a slowly
progressive demyelinating NF1-associated neuropathy or Acknowledgements
does this neurophysiological classification distinguish sepa- We wish to thank Dr Dominique Felten for excellent technical
rate pathophysiological processes? assistance, and Dr Tracy Tucker for improving the English.
 Neurofibromatosis 1 neuropathies 2009

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