Brain Advance Access originally published online on August 2, 2004
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Brain, Vol. 127, No. 9, 1993-2009,
September 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh234
Neurofibromatosis 1-associated neuropathies: a reappraisal
1 Service de Neurologie, 2 Réseau NF-Rhône-Alpin, 3 Service de Dermatologie and 4 Service de Radiologie, Hôpital d'Instruction des Armées Desgenettes, 5 Laboratoire de Génétique Moléculaire, Hôpital Edouard Herriot, Lyon, 6 Réseau NF-Mondor, 7 Service de Dermatologie, 8 Service de Physiologie-Explorations Fonctionnelles, 9 Département de Pathologie, 10 Service de Neuroradiologie, 11 Service de Neurologie, Hôpital Avicenne, Bobigny, 12 Service de Neurochirurgie and 13 Service de Neurologie, Hôpital Henri Mondor, AP-HP, et Université Paris XII, Créteil, France
Correspondence to: Professor Alain Créange, Service de Neurologie, Hôpital Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France E-mail: alain.creange{at}hmn.ap-hop-paris.fr
Received December 1, 2003. Revised February 28, 2004. Second revision on April 19, 2004. Accepted April 23, 2004.
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Summary |
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Neurofibromatosis 1 (NF1) is a common disease which is a source of various multisystemic manifestations related either to the accumulation of neurofibromas or to specific developmental abnormalities. The neurofibroma is the hallmark lesion of NF1 and develops from peripheral nerves. However, to date, the description of peripheral neuropathies of NF1 has not been investigated. To examine this question, we have evaluated 688 NF1 patients for the presentation, prognosis and associated morbidity of peripheral neuropathies in two hospital-based series. We collected 18 patients (four women and 14 men) with diffuse peripheral neuropathy (2.3%). Eight patients had a paucisymptomatic or an asymptomatic neuropathy detected only on electrophysiological study, two had minor sensory manifestations, five had moderate motor and sensory manifestations and three had severe motor and sensory manifestations. Superimposed radicular changes were observed in seven cases. Two patients had a subacute and 16 a chronic polyneuropathy. Fourteen patients had a demyelinating neuropathy with either severe axonal changes (three), moderate or minor axonal changes (four) or no axonal changes (seven). Four patients had axonal neuropathies. There was a strong association between the presence of a peripheral neuropathy and large root diffuse neurofibromas (P < 0.03) and subcutaneous neurofibromas (P < 0.0001). Severe morbidity and mortality of patients with NF1 and peripheral neuropathies was 50%, much higher than what is observed in the general population of patients with NF1, and 100% in patients with the most severe symptoms and electrophysiological changes (demyelination with severe axonal features). Four patients out of 18 (22%) developed a malignant peripheral nerve sheath tumour (MPNST), a much higher proportion than in the whole population of NF1. Two patients died. Peripheral neuropathy constitutes a potentially severe complication in patients with NF1 associated with a frequent morbidity related to spinal complications and MPNSTs. Association of proximal large neurofibromas, peripheral neuropathies and subcutaneous neurofibromas may constitute a phenotype of NF1 with a severe prognosis.
Key Words: 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.
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Introduction |
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TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
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Neurofibromatosis 1 (NF1) is a common genetic disorder characterized by multisystemic manifestations related in part to the accumulation of neurofibromas. Neurofibromas arise from the proliferation of Schwann cells and perineurial fibroblasts in nerve and cutaneous nerve endings. Neurofibromas may be benign, as dermal neurofibromas or plexiform neurofibromas, or malignant, leading to considerable morbidity and mortality, especially in adults (Leroy et al., 2001
). Morbidity associated with benign neurofibromas is dependent on the location of the lesions. When the neurofibromas are located in the cutaneous nerve endings, the main prejudice is aesthetic. When the neurofibromas develop in the subcutaneous nerves, they may lead to chronic disabling pain, considerable dysmorphic changes and may degenerate into malignant peripheral nerve sheath tumours (MPNSTs). Intradural neurofibromas located at the proximal part of the spinal roots are a source of nerve root or spinal cord compressions (Ferner et al., 1989; Riccardi, 1992). These may cause radicular symptoms, including pain, weakness or sensory loss, and, moreover, paraplegia and tetraplegia. Finally, some patients may develop mononeuropathies as a result of nerve compression (Canale et al., 1964). Despite a considerable range of complications related to peripheral nerve development and associated tumours in NF1, the prevalence of peripheral nerve involvement in NF1 is considered rather low in large clinical studies, ranging from 0 to 4.3% of nerve compression and 0 to 2.5% of spinal root compressions (Huson et al., 1988; Riccardi, 1992; Hughes, 1994; Friedman and Birch, 1997; Créange et al., 1999; Ruggieri et al., 1999). Similarly, few cases of polyneuropathies in NF1 have been described (Bielschowsky, 1923; Lambers, 1952; Thomas and Eames, 1971; Bradley et al., 1974; Bosch et al., 1981; Roos et al., 1989; Thomas et al., 1990; Palmowski et al., 1991; Lupski et al., 1993; Hughes, 1994; Ferner et al., 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 peroneal muscular atrophy, the so-called neurofibromatous neuropathy (Thomas et al., 1990), have been reported (Murphy et al., 1980; Thomas et al., 1990; Hughes, 1994) and linked to proliferation of neurofibroma-like tissue (Thomas et al., 1990).
Conversely, peripheral neuropathy in neurofibromatosis 2 has been shown to be much more frequent, with 66.7% electrophysiological abnormalities and 46.7% clinical abnormalities (Sperfeld et al., 2002). Therefore, we have evaluated the peripheral nerve involvement in a series of adult patients with NF1 and report the presentation, classification and prognosis of peripheral neuropathies in a cohort of 18 NF1 patients assessed by electrophysiological, radiological and some pathological features. This study will enlarge the phenotypic spectrum of previously described NF1-associated peripheral neuropathies.
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Patients and methods |
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Patients
Patients were selected from two NF clinics, the Réseau NF-Mondor (383 NF1 patients) and the Réseau NF-Rhône-Alpin (305 NF1 patients). All met the diagnostic criteria for NF1 according to established criteria (National Institutes of Health Consensus Development Conference, 1988
) The patients were ascertained between June 1995 and June 2002 (Réseau NF-Mondor) and between June 1999 and December 2002 (Réseau NF-Rhône-Alpin) using the software of the National Neurofibromatosis Foundation International Database (Vancouver, British Columbia, Canada) (Friedman, 1997). All patients with NF1 were referred to the NF clinic and examined by a physician specialized in NF1 (P.W. and P.C.) and by a neurologist (A.D. and A.C.) if signs or symptoms of neurological involvement were present. We selected patients with clinical symptoms or signs suggesting peripheral nerve involvement, and included those with electrophysiological signs of polyneuropathy. Two additional patients (patients 9 and 18) with myelopathy have been included after a systematic electrophysiological examination.
Clinical study
Information collected regarding the neuropathy included topography of sensory and motor involvement, time course and severity of the neuropathy. Severity of the neuropathy was evaluated as follows: –, asymptomatic or paucisymptomatic; +, minor sensory manifestations; ++, moderate motor and sensory manifestations; and +++, severe motor and sensory manifestations. Other neurological abnormalities, including CNS manifestations, were also recorded.
The following NF1 manifestations were recorded: location of peripheral neurofibromas, i.e. cutaneous and subcutaneous; familial status; and complications of NF1. The follow-up period was recorded when present.
Biological investigations
To consider NF1-associated neuropathy, the patients must have normal or negative results for the following investigations: fasting morning blood glucose level, sedimentation rate, urea, creatinine, serum protein immunoelectrophoresis and quantitative dosage of immunoglobulins, antinuclear antibodies, thyroid-stimulating hormone, vitamin B12 and folate serum levels, human immunodefiency virus (HIV), and hepatitis B and C viruses. According to clinical and electrophysiological presentation, a genetic testing for hereditary motor and sensory neuropathy type 1 was performed.
Electrophysiological study
All data from electrophysiological studies were included in this study. Classification of the neuropathy as axonal or demyelinating was determined according to the criteria of demyelinating neuropathies (Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force, 1991).
Radiological study
All patients except two had an MRI study of the spinal cord and nerve roots. Pelvis–abdominal MRI was performed in 12 patients and chest MRI in five. In nine patients, MRI of the lower limbs was also performed. We evaluated the presence or absence of neurofibromas, and, if present, their location (intradural, foraminal or paraspinal), and distribution (diffuse of focal) along the nerve or nerve roots was also recorded.
Pathological study
When available in our files, superficial peroneal nerve and peroneal frozen muscle biopsy and formalin-fixed samples were examined after staining with haematoxylin and eosin.
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Results |
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Patients clinical histories
Our series included 18 patients (four women and 14 men) with diffuse peripheral neuropathy and NF1, of which 16 had clinical symptoms or signs suggestive of peripheral nerve involvement. Prevalence of symptomatic neuropathies in NF1 was estimated at 2.3% in the cohorts of 688 patients selected from the two NF clinics (1.82% in the Réseau NF-Mondor and 3.6% in NF-Rhône-Alpin). Mean age ± SD of the patients at the time of study was 32.5 ± 13.4 years (range 15–62). Eleven of the 18 patients were new mutations based on family history. Other clinical features of NF1 are summarized in Table 1.
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Patients were classified according to the absence or presence of symptoms and severity of the peripheral neuropathy.
Group 1. Moderate and severe symptomatic neuropathies (patients 1–8)
Patient 1. This 20-year-old man with sporadic NF1 had a previous history of sleep apnoea, tracheal stenosis, hydronephrosis related to compressive neurofibromas and a neck dysmorphy related to subcutaneous neurofibromas. He progressively developed a lower limb distal motor deficit from the age of 16 years. The patient presented with a stepping gait related to a symmetric distal motor deficit of the lower limbs predominating on the dorsal flexor muscles. Distal pain sensation and toe position evaluation was slightly decreased. He had bilateral pes cavus, peroneal atrophy, and ankle and patellar areflexia. Bladder dysfunction with voiding difficulties was also present. Diffuse large neurofibromas were observed on nerve roots (Fig. 1). There was no duplication of the 17q11.2 PMP 22 gene. He had a very slow motor deficit progression during the 4 years of follow-up but, at the age of 24 years, the patient experienced a diffuse enlargement of the neurofibromas of the neck, the mediastinum and the pelvis. He died due to tracheal obstruction related to his neurofibromas.
Patient 2. This 32-year-old man with sporadic NF1 had a 3 month history of increasing gait difficulties that progressively affected his walking capacity. At the time of examination, he was able to walk 100 m with two crutches and had bladder retention dysfunction. Clinical examination showed a severe motor deficit of the lower limbs, a global sensory deficit at T2, lower limb areflexia and a bilateral positive Babinski sign. Spinal MRI examination showed numerous paraspinal neurofibromas along the spinal cord (Fig. 2). Pulse intravenous methylprednisolone induced a transitory improvement in walking capacity and recovery of lower limb stretch reflexes. However, this improvement was brief, as the patient became paraplegic 6 weeks later.
Patient 3. This 16-year-old male with sporadic NF1 presented with a peripheral nerve sheath tumour of the right foot that was treated by chemotherapy (vincristine, ifosfamide, mesna, actinomycine D, methylprednisolone twice then vincristine, ifosfamide, mesna, etoposide once) then 1 month later by an amputation of the limb. After the third course of chemotherapy, he developed a bilateral foot drop, and several weeks later a progressive weakness of both hands. Clinical examination showed a diffuse areflexia, a distal weakness and wasting of the four limb muscles, with lower left limb predominance, and a distal sensory impairment of all modalities. An MRI study showed multiple tumours of various sizes in the peripheral nerves (Fig 3A and B). The patient had a slight clinical and electrophysiological improvement after 1 year. Six months later, he had chest surgery for pulmonary metastasis. He died 1 year later of disseminated metastasis.
Patient 4. This 42-year-old woman with a history of familial NF1 and acute pancreatitis presented with a progressive bilateral four limb weakness and distal paraesthesia for 5 months. Neurological examination showed abolished ankle reflex, biceps reflex and brachioradialis reflex, bilateral motor deficits in the tibialis anterior and peroneal muscles and hand extensor muscles of both hands. There was a stock-like sensory deficit of pain, vibration and touch sensations. Superficial peroneal nerve biopsy was performed and is described later.
Patient 5. This 28-year-old man with a history of sporadic NF1 complained for 3 years of pain in the lateral aspect of the forearms and, more recently, of numbness in the right thumb and left little finger, a progressive weakness of the left shoulder and hands, and paraesthesias in both feet. He had surgery for a pulmonary artery stenosis at 6 years old, was blind in the left eye, and had a palsy of the four lower cranial nerves (IX–X–XI and XII) of the left side with a Horner sign related to a plexiform cervical neurofibroma. Neurological examination showed weakness and wasting of the intrinsic hand muscles, weakness consistent with a left C5–C6 radicular distribution with absence of bicipital reflex and stylo-radial reflex, and no abnormality in the lower limbs. A [18F]fluoro-2-deoxyglucose (FDG) PET scan showed enhancement of the left cervical tumour. Surgery with partial removal of this tumour disclosed an MPNST.
Patient 6. This 51-year-old man with a history of sporadic NF1 had painful gait difficulties, chronic left sciatic pain, retentionary hypoactive bladder dysfunction for 15 years related to a C2–T12 syringomyelia, lower lumbar vertebra and pelvic bone dysplasia, a meningocoel at the left L5 and S1 vertebra, and bilateral pelvic fracture related to osteomalacia. Two large neurofibromas in the right buttock and right thigh were surgically removed 1 year later. In the 2 years preceding the examination, he was progressively confined to a wheelchair because of a progressive hypotonic peripheral paraplegia. On examination, there was a diffuse weakness (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 precluded fine movements of the hands and the capacity to run 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 showed large diffuse neurofibromas of the nerve and nerve roots extending from the pelvis to the feet and a voluminous multilobular tumour of the left thigh (Fig. 4A). FDG PET scanning 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 developed a spastic tetraparesia in a 3 month period. This complication was related to the progression of numerous intradural benign neurofibromas. She previously had exhibited slowing nerve conduction velocities by electrophysiological examination. 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.
Patient 10. This 15-year-old male with familial NF1 experienced pain for several months in the posterior aspects of his thighs and calves while walking. Neurological examination was normal. Symptomatic treatment with amitryptiline decreased the pain. Electrophysiological examination showed decreased conduction velocities in the lower limbs. Genetic testing for PMP 22 gene duplication was negative. MRI showed a diffuse enlargement of lumbar and sacral roots extending into the sciatic nerves (Fig. 5A and B). Cervical echography showed numerous multiple neurofibromas along the vascular axis.
Patient 11. This 20-year-old man with familial NF1 had chronic pain of the anterior aspects of both forearms and thighs for 2 years. Clinical examination showed a distal hypaesthesia of all modalities in the feet, decreased ankle reflexes and a diffuse palpable enlargement of peripheral nerves. MRI examination showed multiple paraspinal tumour masses with bilateral intradural neurofibromas from C1 to C3, and a spinal cord hyperintense signal on T2-weighed images at the C2 level (Fig. 6).
Patient 12. This 43-year-old man with familial NF1 had a right C6 root schwannoma and had experienced painful dysesthesia in the right L4 and S1 territory for several months. Neurological examination was normal, except for a decrease of right bicipital and lower limb reflexes. Two years later, he had increased right cervical pain, whereas clinical examination was unchanged and an FDG PET scan was normal.
Patient 13. This 20-year-old man with sporadic NF1 had a chronic painful left S1 radiculopathy for 18 months related to an extradural neurofibroma. Surgery of this neurofibroma partially decreased the pain. Neurological examination was normal. No change occurred during the following 6 month period.
Patient 14. This 20-year-old man with familial NF1 complained for 3 years of distal and proximal burning pain in the lower limbs. Neurological examination showed decreased stretch reflexes in the lower limbs and altered sensory examination in the feet and legs. MRI showed numerous neurofibromas of lumbosacral roots and nerves (Fig. 7A and B). While neurological symptoms and examination were unchanged, electrophysiological examination 2 years and 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 chronic pain for the past 5 years in the proximal and distal parts of the four limbs, particularly in the right L5 territory, and spastic lower limbs. She had surgery 3 years prior to examination for a C1–C2 spinal cord compression related to bilateral intradural neurofibromas. Neurological examination showed a moderate spasticity of the lower limbs, diffuse hyper-reflexia and bilateral Babinski sign without sensory abnormalities.
Patient 18. A 38-year-old man with a history of familial NF1 with numerous cutaneous and subcutaneous neurofibromas was referred to the NF clinic for follow-up. He had a past history of severe kyphoscoliosis that required surgical correction at the age of 30 years. Unfortunately, it was followed by complete paraplegia at the T9 thoracic level. Treatment of the pyramidal syndrome-associated spasticity required an intrathecal baclofen pump. A systematic electrophysiological examination showed an axonal polyneuropathy.
Investigations
Biological investigations
There was no remarkable biological abnormality in this series of patients, including negative genetic testing for hereditary motor and sensory polyneuropathy type 1 in patients 1 and 10.
Electrophysiological study
Electrophysiological data are reported in Table 2. All patients had a diffuse symmetric polyneuropathy (even if some had superimposed asymmetric changes). The neuropathy involved the four limbs (10 out of 17 patients) or the lower limbs only (seven out of 17 patients). Four patients had an axonal polyneuropathy, and 14 had a neuropathy consistent with either pure demyelinating abnormalities (in seven cases) or associated with axonal changes (in seven cases). Electrophysiological changes were consistent with severe (patients 1, 3 and 6), moderate (patients 2, 7, 11 and 14) or light (patients 5, 8, 10, 12, 13, 15, 16, 17 and 18) axonal or demyelinating abnormalities. Severe changes were associated with severe or moderate clinical symptoms (patients 1, 3 and 6), while moderate or light electrophysiological abnormalities were not associated with a severe clinical neuropathy.
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Radiological study
Patients underwent a radiological investigation of the spine (n = 16), the pelvis (n = 12), chest (n = 5) or limb girdles (n = 9). Fourteen out of 16 patients had diffuse (or multifocal) paraspinal neurofibromas with expansion to intervertebral foramina. Three patients had neurofibromas in the lumbar and sacral roots only. Eight patients had intradural neurofibromas. Of these eight patients, five had a spinal cord compression with clinical (n = 3) or radiological changes (n = 2). Eight out of nine patients had peripheral nerve multinodular images consistent with diffuse neurofibromas of the nerves. Neurofibromas along peripheral nerves appeared as multiple tumour masses with high signal intensity in T2-weighted images and T2 fat saturation images (all patients), with normal or more often low signal intensity in T1-weighted images (Figs 2, 3A and B, and 4A). Five out of seven patients had a slight contrast enhancement of some neurofibromas. Seven out of eight patients, in whom a complete MRI study was performed, had diffuse neurofibromas in the roots, plexus, nerves trunks and nerves endings in muscles and subcutaneous tissue.
Pathological study
In one patient (patient 4), nerve and muscle biopsy was performed and showed the presence of typical neurofibromas. In nerve cross-sections, they appeared in individual fascicles as target-like formations consisting of a central area of compact endoneurial tissue, a ring of loose tissue with myxoid appearance containing sparse collagen bundles, and a peripheral 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 was decreased throughout the fascicles, and myelin sheaths were completely absent in the central zones of the neurofibroma (Fig. 8A and B). In the muscle, neurofibromas appeared as focal areas of endomysial connective tissue swelling with a myxoid appearance, smothering muscle fibres. Muscle neurofibromas were probably developed from nerve twigs. Their borders were ill defined, as commonly observed in cutaneous neurofibromas (Fig. 8C and D).
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Clinical and investigation synthesis
Eight patients had an asymptomatic (patients 9, 12, 13 and 18) or paucisymptomatic (patients 10, 15, 16 and 17) neuropathy (–), with mono- or multiple sensory radiculopathy (patients 10, 12, 13 and 17). Patients 11 and 14 had a mild sensory polyneuropathy (+). Five patients (patients 1, 4, 5, 7 and 8) had moderate motor and sensory neuropathy (++); patient 8 had a moderate mononeuropathy with an asymptomatic polyneuropathy. Three patients (patients 2, 3 and 6) had a severe motor and sensory polyneuropathy (+++). Patients 2, 5 and 6 had an associated polyradiculopathy. While patients 2 and 3 had a peripheral neuropathy with a subacute course, the others had chronic manifestations. Patients 2, 9, 17 and 18 also had spinal manifestations.
Severity of the neuropathy
There was no relationship between the severity of the neuropathy to age, sex, family status, presence or absence of subcutaneous neurofibromas, presence of diffuse large neurofibromas or electrophysiological features. However, severe neuropathies (++ and +++) were more frequently associated with severe complications of NF1, and axonal neuropathies were never associated with severe neuropathies (Tables 1 and 3).
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Patients with demyelinating neuropathies with or without axonal changes did not have a higher risk of severe complication (either MPNST or organ compression) than patients with axonal neuropathies. However, the proportion of severe complications of NF1 for patients with demyelinating neuropathies with severe axonal changes was 100%, whereas for patients with demyelinating neuropathies with moderate axonal changes, pure demyelinating neuropathies and pure axonal neuropathies, the proportion was 50%. Axonal and demyelinating neuropathies were associated with an equivalent delay of neuropathic symptom evolution, of 3 ± 2.1 and 3.4 ± 1 years, respectively.
Morbidity of patients
Ten out of 18 patients had a poor prognosis related either to 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%) developed an MPNST, a much higher proportion than what is observed in the whole population of NF1 (
2 = 8.57; P < 0.004).
Severe NF1 morbidity and mortality were not related to age at the time of neuropathy diagnosis, or duration of neuropathic symptoms, presence of subcutaneous neurofibromas, family NF1 history and gender. However, severe complications of NF1 were more usually observed in patients with severe neuropathies (++ and +++) (Table 3).
In this study, 15 out of 17 patients had subcutaneous neurofibromas, a higher proportion than in the global population of patients with NF1 in the Réseau NF-Mondor (2 = 16.856; P < 0.0001). In addition, 14 out of 16 had proximal neurofibromas, a higher proportion than is estimated in patients with NF1 (82 versus 36–57% of patients, P < 0.03) (Egelhoff et al., 1992; Poyhonen et al., 1997; Tonsgard et al., 1998).
Patients with proximal paraspinal neurofibromas did not have a higher risk of severe complications, i.e. organ compression or MPNST (eight out of 14 patients), than patients without proximal neurofibromas (none out of two) (Fisher's exact test P > 0.05). However, all patients with severe complications had proximal neurofibromas. Diffuse proximal large neurofibromas were not associated with severe neuropathies or with demyelinating or axonal electrophysiological changes.
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Discussion |
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TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
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The peripheral neuropathies observed in this study of 18 patients enlarge the spectrum of the so-called neurofibromatous neuropathy (Thomas et al., 1990
), including patients with asymptomatic polyneuropathy, mildly symptomatic sensory polyneuropathy, slowly progressive sensorimotor polyneuropathy and severe subacute motor predominant polyradiculoneuropathy. Moreover, superimposed radicular changes frequently were associated with the polyneuropathies. Electrophysiological investigations disclosed various patterns of abnormalities from mild sensory axonal polyneuropathy to diffuse subacute motor and sensory demyelinating polyradiculoneuropathy with axonal changes. Ten out of 18 patients had a poor prognosis either related to the neuropathy itself or to an associated life-threatening complication of NF1, such as spinal cord compression by intradural neurofibromas or MPNSTs. These complications were observed specifically in patients with a demyelinating neuropathy with severe axonal changes. A unique pattern of large tortuous nerves related to the proliferation of neurofibromas along nerve trunks was disclosed by MRI investigation of nerves in some patients with peripheral neuropathies, particularly in those with demyelinating features. Finally, the large majority of patients with peripheral neuropathies and NF1 had diffuse proximal neurofibromas and subcutaneous neurofibromas.
Surprisingly, despite its relevance to the clinical spectrum of NF1, there have been no previous publications addressing the question of peripheral neuropathies in NF1, except as case reports [Thomas and Eames, 1971; Bradley et al., 1974 (patient 1); Bosch et al., 1981 (patients 1–4); Roos et al., 1989; Béquet et al., 1990; Thomas et al., 1990 (patient 2); Palmowski et al., 1991; Lupski et al., 1993 (two patients); Hughes, 1994; Ferner et al., 1996; Pascual-Castroviejo et al., 2000]. In other cases reported as NF1-associated neuropathies, 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 the conclusions that can be reached regarding these patients. Paradoxally, the literature is much more detailed on neuropathies associated with NF2, a rarer condition, where 24 patients have been reported [Onishi and Nada, 1972; Thomas et al., 1990 (patient 3); Kilpatrick et al., 1992; Overweg-Plandsoen et al., 1996; Iwata et al., 1998; Gijtenbeek et al., 2001; Hagel et al., 2002; Sperfeld et al., 2002]. The term neurofibromatous neuropathy was first used to describe two patients who had a slowly progressive symmetric distal motor and sensory neuropathy with late childhood onset, and characterized by distal muscle atrophy and pes cavus. These two patients had reduced motor conduction velocities (Thomas et al., 1990). Neurofibromatous neuropathy was considered as a relatively benign condition with a slowly progressive course characterized by a modest disability. Indeed, eight patients in the present series of 18 had an asymptomatic or paucisymptomatic neuropathy, and two had a mild sensory neuropathy. Strikingly, only eight of 13 patients with NF1-associated neuropathy in the literature (Table 4) had the typical presentation of the chronic sensorimotor neuropathy with distal muscular atrophy (seven patients) and pes cavus (three patients) [Thomas and Eames, 1971; Bradley et al., 1974; Murphy et al., 1980; Bosch et al., 1981 (patients 1, 2 and 4); Thomas, 1990; Hughes, 1994]. However, one patient had a chronic motor neuropathy (patient 3 of Bosch et al., 1981) and three had a pure sensory neuropathy (Palmowski et al., 1991; Ferner et al., 1996; Pascual-Castroviejo et al., 2000). In these patients, five had a diffuse enlargement of peripheral nerves. In the present study, three patients experienced severe and four moderate peripheral nerve sensorimotor deficits, while two patients had a subacute course and three patients had an associated poly- or multifocal radiculopathy that does not fit with the relatively benign condition of neurofibromatous neuropathy. In the present study and even more strikingly in the literature, the duration of the neuropathy was longer in cases of moderate/severe neuropathy than in cases of mild neuropathy, with 4.3 ± 5.4 versus 3.2 ± 2.3 years and 15.29 versus 2.33 years, respectively. Large proximal nerves related to the proliferation of proximal neurofibromas seem to constitute a key feature of the majority of patients with NF1-associated neuropathy. Although proximal nerve hypertrophy can be encountered in patients with Charcot–Marie–Tooth disease (Rosen et al., 1989), Déjerine–Sottas disease (Masuda et al., 1992), Noonan syndrome [a genetic disorder that shares features with NF1 (Silburn et al., 1998)], chronic inflammatory demyelinating polyradiculoneuropathy (Aïdi et al., 2002) and NF2-associated neuropathy (Sperfeld et al., 2002), the voluminous deformity of nerves with potential organ compression related to these proliferations is unique for NF1. In the present study, 14 out 16 (87.5%) patients with a peripheral neuropathy had focal or diffuse paraspinal neurofibromas. Diffuse proximal neurofibromas affecting all spinal roots has been considered exceptional and a distinct entity of NF1 (Poyhonen et al., 1997). However, 36–57% of patients with NF1 have spinal neurofibromas (Egelhoff et al., 1992; Poyhonen et al., 1997; Thakkar et al., 1999), and 40% of patients with spinal neurofibromas are asymptomatic (Thakkar et al., 1999). Moreover, whether this condition is associated with asymptomatic peripheral nerve involvement has not been investigated systematically in these patients. Whether these conditions share common genetic determinants remains to be studied.
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Ten out of 18 patients had a severe prognosis (morbidity and mortality) related to the development of MPNST (four patients, one death), spinal cord (five patients) or organ compressions (two patients, one death) or to the neuropathy itself (three patients). This represents a higher proportion than in a population of patients with NF1 (Huson et al., 1988
; Riccardi, 1992; Créange et al., 1999) especially for MPNST (22% in this series).
Interestingly, there is an association between peripheral neuropathy and subcutaneous neurofibromas, which have been shown to be an independent life prognosis factor in patients with NF1 (Khosrotehrani et al., 2003), highlighting the potentially poor prognosis of patients with NF1-associated neuropathy and subcutaneous neurofibromas.
The axonal features of the so-called neurofibromatous neuropathy are not consistent with several patients reported in this study. Indeed, the majority of patients with a bad prognosis had demyelinating electrophysiological features, whereas only half of the patients with axonal features had life-threatening complications. Moreover, patients with pure demyelinating changes had fewer complications than patients with demyelinating neuropathies and severe axonal features. Does axonal changes constitute a late stage of a slowly progressive demyelinating NF1-associated neuropathy or does this neurophysiological classification distinguish separate pathophysiological processes?
Nerve biopsy findings in NF1, reported in the literature, show various features including macroscopic extensive nodular thickened nerves (five out of eight patients), neurofibromatous tissue (five), loss of myelinated fibres (seven) and even onion bulb formations (two). Giant neurofibromas at the root level (Figs 6 and 7A), multiple neurofibromas along the nerve (Figs 3A and B, 4A, and 5A and B) and intraneural proliferation of neurofibroma-like tissue distally (Fig. 8A) may produce compression along roots and nerves. This phenomenon may induce axonal degeneration and multifocal myelin sheath loss along the nerve (Fig. 8B) that may explain the varied combination of compound muscle action potential amplitude decrease and slow motor nerve conduction velocities on electrophysiological examination. Moreover, associated factors, such as chemotherapy in patient 3 or inflammatory changes in patients with demyelinating neuropathies, may disclose or increase the severity of an asymptomatic neuropathy. In another way, a random association with a CMT1a neuropathy—a genetic location on the mirror segment of chromosome 17—as in two patients in the literature (Lupski et al., 1993), could account for some cases of demyelinating neuropathies. Other unknown local toxic or metabolic factors, as in NF2 (Sperfeld et al., 2002), could also be hypothesized in NF1. Finally, the presence of one or several specific factors stimulating abnormal Schwann cell development inducing myelin changes, giant neurofibromas and favouring MPNST onset may account for the association observed in the present study. A circulating factor may well facilitate the development of neurofibromas in the nerve roots, where the blood–nerve barrier is weaker. Finally, the presence of subcutaneous neurofibromas in patients with NF1-associated neuropathy suggests that development of giant proximal neurofibromas, peripheral nerve changes and subcutaneous neurofibromas may be included in a phenotype of deep neurofibromas that may be related to specific genetic alterations that may lead to the development of MPNST.
It appears that NF1-associated neuropathy is a rare condition when polyneuropathy is symptomatic. The prevalence of paucisymptomatic and asymptomatic forms could be more frequent. It is not a benign condition that can be characterized in some cases by an acute or subacute course, and is associated with a high prevalence of life-threatening complications. Peripheral neuropathy should be screened for in patients with NF1, particularly those with subcutaneous neurofibromas. Demyelinating features with progressive appearance of axonal features should alert one to the potential development of MPNST or organ compression, and mandate a clinical or radiological follow-up. Whether systematic electrophysiological investigations are required to evaluate the potential risk of MPNST remains to be investigated.
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We wish to thank Dr Dominique Felten for excellent technical assistance, and Dr Tracy Tucker for improving the English.
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