Neurofibromatosis 1-associated neuropathies: a reappraisal

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1 Brain Advance Access published August 2, 2004 DOI: /brain/awh234 Brain Page 1 of 17 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, 1 Pascal Ehre, 4 Philippe Decq, 6,12 and Alain Créange 6,13 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 Summary Neurofibromatosis 1 (NF1) is a common disease which is a source of various multisystemic manifestations related either to the accumulation of 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 hospitalbased 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. Fourteen patients had a neuropathy with either severe axonal changes Correspondence to: Professor Alain Créange, Service de Neurologie, Hôpital Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, Créteil, France alain.creange@hmn.ap-hop-paris.fr (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 (P < 0.03) and subcutaneous (P < ). 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, peripheral neuropathies and subcutaneous may constitute a phenotype of NF1 with a severe prognosis. Keywords: neurofibromatosis 1; peripheral neuropathy; demyelination; malignant peripheral nerve sheath tumour Abbreviations: FDG = [ 18 F]fluoro-2-deoxyglucose; MPNST = malignant peripheral nerve sheath tumour; NF1 = neurofibromatosis 1. Received December 1, Revised February 28, Second revision April 19, Accepted April 23, 2004 Brain # Guarantors of Brain 2004; all rights reserved

2 Page 2 of 17 A. Drouet et al. Introduction Neurofibromatosis 1 (NF1) is a common genetic disorder characterized by multisystemic manifestations related in part to the accumulation of. Neurofibromas arise from the proliferation of Schwann cells and perineurial fibroblasts in nerve and cutaneous nerve endings. Neurofibromas may be benign, as dermal or plexiform, or malignant, leading to considerable morbidity and mortality, especially in adults (Leroy et al., 2001). Morbidity associated with benign is dependent on the location of the lesions. When the are located in the cutaneous nerve endings, the main prejudice is aesthetic. When the 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 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. Patients and methods 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. 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; þ, minor sensory manifestations; þ þ, moderate motor and sensory manifestations; and þþþ, severe motor and sensory manifestations. Other neurological abnormalities, including CNS manifestations, were also recorded. The following NF1 manifestations were recorded: location of peripheral, 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 was determined according to the criteria of

3 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, 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. Results 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 6 SD of the patients at the time of study was 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. 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 and a neck dysmorphy related to subcutaneous. 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 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 Neurofibromatosis 1 neuropathies Page 3 of 17 the of the neck, the mediastinum and the pelvis. He died due to tracheal obstruction related to his. 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 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 stocklike 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.

4 Page 4 of 17 A. Drouet et al. 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 Age (years) Age at onset of neuropathy (years) Sex M M M F M M M F F Family history No No No Yes No No No Yes No Cutaneous NA 0 > Subcutaneous >2 >2 >2 NA >2 >2 >2 >2 >2 Peripheral nerve Distal lower Proximal and Distal four limb Distal four limb Weakness of Proximal and Distal Lower left foot symptoms and limb symmetric distal lower symmetric symmetric intrinsic hand distal lower limb symmetric four pain and motor signs, other motor and limb symmetric motor and motor and muscles, of left symmetric limb sciatic deficit neurological stock-like motor deficits, sensory stocklike sensory stock- C5 C6 muscles, motor deficits, sensorimotor manifestations sensory deficits; T2 sensory 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 classification Root Peripheral nerve location of the neuropathy with severe axonal features of the four limbs fo/para at Ce, Th, Lu,Sa levels (Fig. 1) NF1 complications Hydronephrosis, sleep apnoea and tracheal stenosis, related to neurofibroma compression. Death at 24 y.o secondary to tracheal stenosis Peripheral neuropathy classification neuropathy with moderate axonal features of the four limbs id/fo/para at Ce, Th, Lu levels (Fig. 2) neuropathy with severe axonal features of the four limbs fo/para at Th, Sa levels NA NA Plexus, intercostal, upper and lower limb peripheral nerves (Fig. 3A and B) Chronic (with axonal features) Paraplegia related to neurofibroma compression of lower limb roots and spinal cord Subacute polyradiculoneuropathy (cauda equina syndrome), spinal cord compression Scoliosis, meningocoel, MPNST (16 y.o). Death at 18 y.o. Subacute (with axonal features) the four limbs the four limbs NA Diffuse fo/para at Ce, Th, Lu, Sa levels NA Plexus and intercostal nerves None Left eye blindness, spheno-orbital dysplasia, cerebral hamartoma, cervicomediastinal MPNST Chronic Chronic in the upper limbs with severe axonal features in the lower limbs fo/para at Sa levels the four limbs with moderate axonal changes the lower limbs and severe left sciatic neuropathy Spastic tetraparesia neuropathy Diffuse fo/para Diffuse fo/para id cervical and diffuse fo/para NA NA Lumbo-sacral plexus and lower limbs Syringomyelia from C1 to S2, L5 vertebra dysplasia, and sacral lyses Chronic polyradiculoneuropathy with severe axonal changes None Voluminous left sciatic nerve MPNST (Fig. 4A) Chronic sensorimotor with moderate axonal changes Mononeuropathy with subclinical NA Partial spinal cord compression with spastic tetraparesia. MPNST Asymptomatic

5 Neurofibromatosis 1 neuropathies Page 5 of 17 Table 1 Continued Patient 10 Patient 11 Patient 12 Patient 13 Patient 14 Patient 15 Patient 16 Patient 17 Patient 18 Age (years) Age at onset of neuropathy (years) Sex M M M M M M M F M Family history Yes Yes Yes No Yes No No No Yes Cutaneous > >100 Subcutaneous 2 >2 >2 >2 >2 0 0 >2 >2 Peripheral nerve Pain in thighs Stock-like Painful Painful left S1 Stock-like Pain in the distal Painful Pain in the distal symptoms and signs, and calves while sensory deficits, dysesthesias in radiculopathy sensory deficits, parts of the dysaesthesias in part of the four 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 þ þ Severity of the neuropathy Electrophysiological classification the lower limbs Root fo/para at Lu, Sa levels Peripheral nerve locations of the Lu, Sa plexus and lower limbs (sciatic nerves) (Fig. 5A and B) the four limbs with mild axonal features fo/para at Ce (id C1 C3), Th, Lu, Sa levels (Fig. 6) Plexus, intercostal, lower and upper limb nerves NF1 complications None Asymptomatic C2-spinal MRI abnormality Peripheral neuropathy classification Paucisymptomatic Chronic sensory the lower limbs fo/para at Ce, Th (id 4,6, 8), Lu, Sa levels. Lumbo-sacral plexus, lower limb and intercostal nerves Large C6 right root schwannoma surgically removed Right L4/S1 radiculopathies and asymptomatic the four limbs fo/para at Sa levels Lumbo-sacral plexus and lower limb nerves Left paraspinal S1 neurofibroma surgically removed Left S1 radiculoneuropathy and asymptomatic the lower limbs with mild axonal features fo/para at Th, Lu, Sa levels (Fig. 7A and B) Lumbo-sacral plexus and proximal part of lower limb nerves, intercostal nerves Asymptomatic compression of vessels and pelvis viscera Chronic sensory with mild axonal features Axonal sensory of the four limbs Axonal sensory the lower limbs Axonal the lower limbs None None Diffuse at fo/para from Ce to Sa levels, id at Ce levels NA None Plexus, upper and lower limb, and intercostal nerves None None Right blindness, C2 myelopathy secondary to id. Chronic sensory painful axonal Chronic axonal sensory Chronic lower limb sensory axonal Thoracic 9 level paraplegia Axonal the lower limbs NA NA Spastic paraplegia as a complication of kyphoscoliosis surgery Asymptomatic axonal 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.

6 Page 6 of 17 A. Drouet et al. Fig. 1 MRI examination of the chest showing enlargement of the thoracic roots and diffuse large proximal of the thoracic nerves (patient 1) (T2-weighted image). sensorimotor. Fig. 2 Frontal MRI image of the lumbar roots and plexus (patient 2) showing diffuse proximal large (T1-weighted image). sensorimotor. A [ 18 F]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 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 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 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. 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 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 from C1 to C3, and a spinal cord hyperintense signal on T2-weighed images at the C2 level (Fig. 6).

7 Neurofibromatosis 1 neuropathies Page 7 of 17 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 are visible all along the nerves. sensorimotor. Fig. 4 (A) Bilateral sagittal images of the thighs showing diffuse proliferation of 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. (B) The FDG PET scanning showed a intense contrast enhancement consistent with the left sciatic nerve malignant tumour. neuropathy with sciatic nerve deficit. 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

8 Page 8 of 17 A. Drouet et al. 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 neuropathy. Fig. 6 Hyperintense bilateral intra-axial and foraminal tumour masses at the C2 level with right spinal cord hyperintense signal (cervical axial image in T2 fat saturation sequence). Mild sensory. 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 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 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. 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 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

9 Neurofibromatosis 1 neuropathies Page 9 of 17 Fig. 7 (A) Large proximal 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 (T2 fat saturation image of thoracic coronal section). Mild sensory. intrathecal baclofen pump. A systematic electrophysiological examination showed an axonal. Investigations Biological investigations There was no remarkable biological abnormality in this series of patients, including negative genetic testing for hereditary motor and sensory type 1 in patients 1 and 10. Electrophysiological study Electrophysiological data are reported in Table 2. All patients had a diffuse symmetric (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, and 14 had a neuropathy consistent with either pure 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 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. 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 with expansion to intervertebral foramina. Three patients had in the lumbar and sacral roots only. Eight patients had intradural. 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 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. Seven out of eight patients, in whom a complete MRI study was performed, had diffuse 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. 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, appeared as focal areas of endomysial connective tissue swelling with a myxoid appearance, smothering muscle fibres.

10 Page 10 of 17 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 Median nerve Amplitude-thenar (mv) > / / Distal latency (ms) < / / velocity-forearm (m/s) > /40 32/ F wave latency (ms) < /37.2 0/ Ulnar nerve Amplitude-hypothenar (mv) > / / Distal latency (ms) < / / velocity-forearm (m/s) > /33 32/ F wave latency (ms) < / / Radial nerve Amplitude-forearm (mv) >3 velocity-elbow (m/s) > Common peroneal Amplitude-foot (mv) > / 0/ Distal latency (ms) < / 0/ velocity-leg (m/s) > / 0/ F wave latency (ms) < / 0/ Tibial nerve Amplitude-foot (mv) > / 0.2/ Distal latency (ms) < / 10.4/ nerve velocity-leg (m/s) > / 26/ F wave latency (ms) < / 0/ Sensory nerve conduction Median nerve Amplitude (mv)> / / velocity-wrist (m/s) > /47 40/ Ulnar nerve Amplitude (mv) >9 3 4 /3.3 / velocity-wrist (m/s) > /44 / Radial nerve Amplitude (mv) >15 /6.2 / velocity-forearm >40 /52 / Superficial peroneal nerve Amplitude (mv) >8 0 0 / 0/ velocity-ankle (m/s) > / 0/ Sural nerve Amplitude (mv) > / 0/ velocity-ankle (m/s) > / 0/ 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) > Distal latency (ms) < velocity-forearm (m/s) > F wave latency (ms) < Ulnar nerve Amplitude hypothenar (mv) >

11 Neurofibromatosis 1 neuropathies Page 11 of 17 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) < velocity-forearm (m/s) > F wave latency (ms) < Radial nerve Amplitude-forearm (mv) > > velocity-elbow (m/s) Common peroneal Amplitude-foot (mv) > Distal latency (ms) < velocity-leg (m/s) > F wave latency (ms) < Tibial nerve Amplitude-foot (mv) > Distal latency (ms) < nerve velocity-leg (m/s) > F wave latency (ms) < Sensory nerve conduction Median nerve Amplitude (mv) > > velocity-wrist (m/s) Ulnar nerve Amplitude (mv) > > velocity-wrist (m/s) Radial nerve Aplitude (mv) > > velocity-forearm Superficial peroneal nerve Amplitude (mv) > > velocity-ankle (m/s) Sural nerve Amplitude (mv) > > 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 contraction Yes No Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes NA NA *First/second examination. NA = not able to perform. Muscle were probably developed from nerve twigs. Their borders were ill defined, as commonly observed in cutaneous (Fig. 8C and D). 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 (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. Three patients (patients 2, 3 and 6) had a severe motor and sensory (þþþ). Patients 2, 5 and 6 had an associated polyradiculopathy. While patients 2 and 3

12 Page 12 of 17 A. Drouet et al. 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 consisting of endomysial connective tissue swelling with a myxoid appearance as commonly observed in cutaneous. 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, presence of diffuse large or electrophysiological features. However, severe neuropathies (þþ and þþþ) were more frequently associated with severe complications of NF1, and axonal neuropathies were never associated with severe neuropathies (Tables 1 and 3). Patients with 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 neuropathies with severe axonal changes was 100%, whereas for patients with neuropathies with moderate axonal changes, pure neuropathies and pure axonal neuropathies, the proportion was 50%. Axonal and neuropathies were associated with an equivalent delay of neuropathic symptom evolution, of and 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 (x 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, family NF1 history and gender. However, severe complications of NF1 were more usually observed in patients with severe neuropathies (þþ and þþþ) (Table 3). In this study, 15 out of 17 patients had subcutaneous, a higher proportion than in the global population of patients with NF1 in the Réseau NF-Mondor (x 2 = ; P < ). In addition, 14 out of 16 had proximal, 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 did not have a higher risk of severe complications, i.e. organ compression or MPNST (eight out of 14 patients), than patients without proximal (none out of two) (Fisher s exact test P > 0.05). However, all patients with severe

13 Neurofibromatosis 1 neuropathies Page 13 of 17 Table 3 NF1 features and complications (i.e. organ/spinal cord compression or MPNST) according to the severity of the neuropathy Moderate and severe neuropathies Asymptomatic, paucisymptomatic and mild neuropathies P Patients (number) NS Age (years) NS Delay of evolution (years) NS Sex (M : F) 6 : 2 8 : 2 NS Family history 4/9 (44.4) 2/9 (22.2) NS Subcutaneous (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 features 7/7 (100%) 6/10 (60%) NS Pure 2/7 4/10 With axonal features 5/7 2/10 Diffuse proximal 7/7 (100%) 7/9 (78%) NS complications had proximal. Diffuse proximal large were not associated with severe neuropathies or with or axonal electrophysiological changes. Discussion 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, mildly symptomatic sensory, slowly progressive sensorimotor 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 to diffuse subacute motor and sensory 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 or MPNSTs. These complications were observed specifically in patients with a neuropathy with severe axonal changes. A unique pattern of large tortuous nerves related to the proliferation of along nerve trunks was disclosed by MRI investigation of nerves in some patients with peripheral neuropathies, particularly in those with features. Finally, the large majority of patients with peripheral neuropathies and NF1 had diffuse proximal and subcutaneous. 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

14 Page 14 of 17 A. Drouet et al. Table 4 Neurological, cutaneous and demographic features of NF1-associated neuropathy in the literature Lambers (1952) Thomas and Eames (1971) Bradley et al. (1974) case 1 Bosch et al. (1981) case 1 Bosch et al. (1981) case 2 Bosch et al. (1981) case 3 Bosch et al. (1981) case 4 Age (years) NS Age at onset of NS NA NA 19 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 Subcutaneous Peripheral nerve symptoms and signs, other neurological manifestations Electrophysiological classification Roots Nerve biopsy findings Complications of NF1 NS Yes yes yes NS NS yes NS Chronic distal symmetric sensorimotor and progressive PN of the four limbs. Amyotrophy NS Lower limb denervation. Reduced nerve conduction velocities in the upper limbs Chronic distal symmetric sensorimotor progressive PN of the four limbs. Amyotrophy. Thick ulnar nerves NS NS. EN Multiple id at Ce and upper Th levels; normal CSF Diffuse thickening; degeneration of nerve fibres; mucoid interstitial material Compact endoneurial tissue with loss of myelinated fibres; neurofibromatosis tissue Chronic distal symmetric sensorimotor progressive PN of the four limbs. Severe amyotrophy and PC. Walking impaired at 26 years old Axonal neuropathy Slow nerve conduction velocities in the median nerve ( 40%) Endoneurial proliferation of linear Schwann cells. Loss of myelinated nerve fibres NS no Deafness, mutism, partial albinism, iris abnormalities Chronic distal symmetric motor predominant progressive PN of the four limbs. Amyotrophy and PC. Tandem gait Slow nerve conduction velocities in the median nerve ( 20%) Distal lower limb motor neuropathy with amyotrophy Chronic distal symmetric sensorimotor progressive PN of the lower limbs. Amyotrophy NS Slow nerve conduction velocities in the median nerve ( 20%) No NS NS Normal cervical myelography Loss of myelinated fibres. Onion bulbs; increased endoneurial connective tissue. Clusters of regenerating myelinated nerve fibres Congenital deafness and mutism at 5 years old (normal cerebral CT scan) Similar to preceding Bosch case with more onion bulbs and clusters of regenerating myelinated nerve fibres Deafness in adolescence (normal cerebral CT scan) NS NS Generalized seizures (onset at 21 years old) Mild thoracic scoliosis

15 Neurofibromatosis 1 neuropathies Page 15 of 17 Roos et al. (1989) Thomas et al. (1990) case 2 Palmowski et al. (1991) Hughes (1994) Ferner et al. (1996) Pascual- Castroviejo et al. (2000) Age (years) Age at onset of the neuropathy (years) Sex M M F M M F Family history No Yes No NS NS No Cutaneous No Yes No NS NS No Subcutaneous Yes Yes Yes NS NS Yes Peripheral nerve Chronic distal symptoms and signs, sensory PN of other neurological the four limbs manifestations Electrophysiological classification Chronic distal symmetric sensorimotor progressive PN predominating in the lower limbs. Amyotrophy Slow nerve conduction velocity in tibial nerve. Absence of sensory potentials in the lower limbs Roots fo L3 to S1, id L4 L5, brachial and lumbosacral plexus, femoral and sciatic nerves Nerve biopsy findings Complications of NF1 Bilateral plexiform of the Lu-Sa nerves roots Asymptomatic compression by of bladder and colon Chronic distal symmetric sensorimotor progressive PN predominating in the lower limbs. Amyotrophy EN, PC Reduced nerve conduction velocities in upper limbs. Absence of sensory potentials in the upper limbs Chronic distal paraesthesias in the hands and feet. Multifocal sensory painful nodes. Normal neurological examination except painful EN Reduced nerve conduction velocities Subacute/ chronic progressive sensori-motor PN with peroneal atrophy Axonal of the lower limbs Predominantly sensory axonal neuropathy Chronic pain in nerve trunk territories with painful irregular EN. Diffuse areflexia Reduced motor conduction velocities of the lower limbs. Absence of sensory potentials NA NS Yes NS fo Ce to Sa, intercostals nerves and limbs Similar to the case of Thomas and Eames (1971) Myelinated fibre loss, nerve sprouting, fibrous tissue No No Enlargement of at 34. Death at 35 years old from malignant peripheral nerve sheath tumour NS Multifocal neurofibromatous tissue and variable reduction in myelinated nerve fibre density NS No Enlargement of the left optic nerve EN = diffuse enlargement of peripheral nerve; PN = ; 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.