TY - JOUR
AU - Hanemann, C., O.
AB - Abstract Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder characterized by the occurrence of bilateral vestibular schwannomas, various brain and spinal tumours as well as peripheral nerve tumours, cutaneous tumours and juvenile posterior lenticular opacity. NF2 is caused by mutations in both alleles of a tumour suppressor gene coding for a protein called schwannomin or merlin. It is suggested that the development of NF2 tumours is caused by complete inactivation of the merlin/schwannomin gene. Interest ingly, in a NF2 mouse model, peripheral nerve pathology was more frequently described than schwannomas. However, review of the literature shows that patients suffering from NF2 seldom have unexplained clinical features of peripheral nerve lesion unrelated to tumour masses. Single case reports describe sural nerve biopsies, which histologically show onion‐bulb‐like formations, seemingly originating from Schwann cells. We have conducted a systematic investigation to determine the occurrence and aetiology of peripheral nerve involvement in NF2 patients. We investigated 15 patients with definite NF2 and in 10 of these found electrophysiological evidence of neuropathy. In this study we present the classification of neuropathy, correlation to clinical findings, and histological findings of a sural nerve biopsy. We conclude that peripheral neuropathy, mostly of axonal type, is a common clinical finding in NF2. We hypothesize that the aetiology of this frequent peripheral neuropathy syndrome in NF2 is caused by compression effects of multiple tumourlets, originating along the length of the peripheral nerves on adjacent nerve fibres, by local influences of the endoneurial pathological cells on adjacent nerve fibres and/or the inability of these cells to properly adhere to, or ensheath, the axon. Keywords: neurofibromatosis type 2; peripheral neuropathy; preneoplasia Abbreviations: CMAP = compound motor action potential; DML = distal motor latency; NCV = nerve conduction velocity; NF2 = neurofibromatosis type 2; SNAP = sensory nerve action potential Received April 30, 2001. Revised August 6, 2001. Second revision November 7, 2001. Accepted December 6, 2001 Introduction Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder with almost full penetrance and a high rate of sporadic occurrence (Evans et al., 1992c; Evans et al., 2000). Stringent diagnostic criteria differentiate NF2 from neurofibromatosis type 1, formerly known as von Recklinghausen’s disease or peripheral neurofibromatosis: the occurrence of bilateral vestibular schwannomas and additional manifestations include various CNS tumours including meningiomas, schwannomas of other cranial nerves, astrocytomas, ependymomas, as well as juvenile posterior lenticular opacity and, to a lesser extent, peripheral nerve tumours, cutaneous tumours and rare café‐au‐lait spots (Kanter et al., 1980; Martuza et al., 1988; Mautner et al., 1995; Gutmann et al., 1997). NF2 is caused by mutations in a tumour suppressor gene coding for a protein referred to as schwannomin or merlin (Rouleau et al., 1993; Trofatter et al., 1993). Analysis of NF2 mutations has revealed some general genotype/phenotype correlations, and severe disease has been associated with mutations that produce a premature termination of translation, while milder disease forms have been related to missense mutations (Evans et al., 1998; Gutmann et al., 1998; Evans et al., 2000; Giovannini et al., 2000). Additionally, somatic mutations in the second wild‐type allele (second hit) of the NF2 gene are found in both sporadic and familial schwannomas and meningiomas (Gutmann, 1997; MacCollin and Gusella, 1998). It is suggested that the development of these tumours is caused by complete inactivation of the merlin/schwannomin gene, one mutation occuring constitutively in almost all cells and the second hit in tumour cells, e.g. Schwann cells. Interestingly, polyneuropathy is reported to occur rather infrequently and has been described in only a few case studies of NF2. In a large clinical study, peripheral nerve lesions unrelated to tumour masses were observed in 6% of patients suffering from NF2 (Evans et al., 1992a). The few case reports include patients suffering from definite NF2 and focal amyotrophy, distal symmetric sensorimotor neuropathy, or mononeuritis multiplex (Bosch et al., 1981; Kilpatrick et al., 1992; Overweg‐Plandsoen et al., 1996; Iwata et al., 1998). Sural nerve biopsies in selected cases showed the histological appearance of so‐called ‘coreless onion bulb’ formations (Onishi et al., 1972; Thomas et al., 1990; Iwata et al., 1998). The observation that many patients with NF2 present with areflexia, which cannot be completely explained by tumour burden, suggests that subclinical neuropathy is under‐recognized and that Schwann cells outside schwannomas might be involved in NF2 (MacCollin, 1999). In this context, the comparatively frequent occurrence of skin tumours as opposed to the infrequent occurrence of peripheral neuropathy is surprising (Evans et al., 1992a; Parry et al., 1994). We therefore conducted a systematic investigation to determine the prevalence of peripheral neuropathy in NF2. In this study we investigated 15 patients suffering from definite NF2 and estimated the frequency and type of neuropathy in correlation to clinical, MRI and laboratory findings. In addition, the fine structural pathological hallmarks of a sural nerve biopsy are described. Methods Patients Patients were continuously recruited from our neurofibromatosis outpatient clinic. All patients fulfil the criteria for definite NF2 (Gutmann et al., 1997). Patients gave informed consent to participate in the study which was approved by the local Ethics Committee. Clinical and detailed neurological examination, including cutaneous inspection and strength assessment using the Medical Research Council Scale, was carried out. Touch sensation and vibration were tested with a monofilament and a tuning fork, respectively. Descriptions are focused on medical history and current symptoms related to NF2, with a special emphasis on skin manifestations and symptoms related to a probable peripheral neuropathy. In case of clinical evidence for a peripheral neuropathy, the neuropathy was graded as: (i) mild (absent ankle jerks, slight symmetrical hypaesthesia, impaired pallaesthesia); (ii) moderate (signs as in mild neuropathy plus atrophy of distal muscles or deformities of the foot); or (iii) severe (signs as in moderate neuropathy plus trophic disturbances, analgesia, loss of sensory modalities). Additional signs and aspects in the medical history of the patients are also mentioned where relevant. MRI of the thoracal spinal cord and actual status of vestibular schwannomas are not described. Neurophysiology Nerve conduction velocity (NCV) studies and EMG methods followed standard techniques using the electromyograph Multiliner® Evolution 1.63 (Jaeger/Toennies, Hoechberg) (Kimura, 1989). Sensory nerve conduction studies were performed antidromically for the sural nerve and orthodromically for the median nerve, at least on one side. Motor nerve conduction studies were also done at least on one side on the median and the tibial nerves. Semiquantitative EMG was performed with concentric needle electrodes on the tibialis anterior muscle and, in cases in which a neurogenic pattern was found, an additional EMG of the gluteus medius muscle was performed. Laboratory analysis In all patients with electrophysiological evidence for neuropathy we attempted to obtain the following laboratory data: level of urea, creatinine, C‐reactive protein, homocysteine, serum folate, methylmalonic acid, glyco‐haemoglobin or fasting morning blood glucose levels, levels of free triiodothyronine, free thyroxine and thyrotropin, quantitative estimation of immunoglobulin subclasses G, A and M, serum electrophoresis, anti‐Borrelia burgdorferi antibodies, ANA (antinuclear antibodies), HIV‐infection diagnosis and Treponema pallidum microhaemagglutination assay. In case of an abnormal test result, further investigations were undertaken, e.g. estimation of ENA (epithelial cell‐derived neutrophil‐activating protein). Neuroimaging For brain imaging, sagittal, coronal, and transversal T1‐weighted and T2 sequences were examined. For spine imaging, sagittal T2‐weighted sequences, as well as sagittal and transverse T1‐weighted sequences were obtained. T1‐weighted transverse and sagittal images were also obtained with intravenous administration of gadopentetate dimeglumine. All MRI images were assessed by independent radiologists. Tumours were assessed for their number, location, morphology and signal characteristics on the T1‐ and T2‐weighted images, and for signal behaviour before and after administration of contrast medium. In Case 7, only CT was performed because of a brainstem implant. Sural nerve biopsy A sural nerve specimen 1.6 cm in length was used for paraffin embedding and H&E (haematoxylin–eosin) staining of sections, and for epoxy resin embedding. Semi‐thin sections of these plastic embedded blocks were stained with paraphenylenediamine and toluidine blue. Ultrathin sections were contrast enhanced with lead citrate and uranyl acetate for electron microscopy using routine methods. Results We have conducted a systematic investigation to determine the occurrence and aetiology of peripheral nerve involvement in NF2 patients. We investigated 15 patients with definite NF2 and in 10 patients found evidence of neuropathy. Clinical characteristics Fifteen patients (seven females, eight males) were investigated. The mean age at evaluation was 37.9 years (range 27–57 years). Clinical information relevant in respect to peripheral neuropathy is given below. Other NF2 features, including MRI findings and patients with neither clinical nor electrophysiological evidence of polyneuropathy, are summarized in Table 1. Case 1 From age 34 years, this patient had observed exercise‐induced muscle cramps with distal predominance in the legs, progredient balance and non‐specific sensory disturbances. At that time, actual neurological examination revealed signs of mixed sensory and motor neuropathy. This patient carried a non‐sense mutation (C784T). Case 2 From her early teens this 28‐year‐old female had bilateral cramps in the calves, impaired balance, mild paresis of the peroneal muscles, and dysaesthesia and hypaesthesia of the lower extremities with distal predominance. A ‘polyneuropathy’ was diagnosed. Clinical and neurological investigation showed absent tendon reflexes, plegia of the anterior tibialis and peroneal muscles, severe paresis of the calf muscles and of the bilateral intrinsic hand muscles. In addition, distal analgesia and severe hypaesthesia of the lower extremities and, following cutaneous innervation, areas of peripheral nerves in upper extremities were observed. MRI of the lumbar spinal cord showed multiple tumour masses of various size involving multiple nerve roots of the cauda equina. In addition, MRI of the lumbar plexus revealed enlarged tumours along both sciatic nerves down to the sciatic foramen. Case 3 The parents of this patient noted bilateral foot deformity (pes cavus) since childhood. On neurological examination he showed a slightly unsteady gait, normal sensory modalities (except for a right‐accentuated impaired vibration sense of hand and foot), and mild weakness and wasting of intrinsic foot muscles, anterior tibialis and peroneal muscles. The deep tendon reflexes were sluggish. Case 4 Clinical investigation showed absent ankle jerks, discrete bilateral paresis of anterior tibialis and peroneal muscles, and reduced vibration sense at lower extremities in this patient. Case 5 This 22‐year‐old female had a 10‐year history of sudden onset progressive left thigh weakness and wasting. Occasional fasciculations were evident. Later in life weakness of the lower extremities progressed. MRI of the lumbar spine showed an intradural schwannoma affecting the left‐sided fourth and fifth nerve root and a left‐sided extraforaminal schwannoma at the second lumbar nerve root. After extirpation of tumour, clinical symptoms remained unchanged. Neurological examination showed profound wasting of the left gluteus medius, quadriceps and iliopsoas muscle, an absent left knee jerk, bilateral reduced vibration sense of the lower extremities, and stand and gait ataxia. Case 6 On neurological evaluation, gait disturbance, mild reduced vibration sense and absent ankle jerks were found. Case 7 Detailed neurological examination showed mild stand and gait ataxia, and reduced ankle jerks. Other deep tendon reflexes, muscle strength and sensory function were normal except for hypaesthesia of all right fingertips. Cases 8–15 In Cases 8–15 no clinical evidences for a neuropathy were found. In summary, clinical investigation showed a motor and/or sensory distal peripheral neuropathy in seven of 15 patients (46.7%). One patient clinically presented with mononeuropathy multiplex. Following grading there were four patients with a mild, two patients with a moderate and one patient with a severe neuropathic syndrome. According to previously published criteria, severity of grading in NF2 is based on tumour burden and age of onset (Evans et al., 1992c; Parry et al., 1994). Following these criteria, all patients except one had a severe form of NF2, although few had late onset (which is one criterion) or a mild form. One patient with mild NF2 showed no evidence for neuropathy. One patient (Case 3) showed bilateral foot deformities from early childhood. Two patients (Cases 2 and 3) suffered from neuropathic syndrome years before they experienced common symptoms due to NF2 (Table 1). Electrophysiological findings NCV studies were performed in all patients with neuropathy. Table 2 summarizes the results of motor and sensory nerve conduction studies. Electrophysiologically, all patients had a symmetric polyneuropathy. Table 2 shows the classification of neuropathies. Ten patients (66.7%) revealed electrophysiological evidence of neuropathy. Electrophysiological findings were often moderate but unambiguous. There were seven patients with axonal neuropathy, one patient (Case 3) with a demyelinating neuropathy and two patients (Cases 6 and 9) suffered from mixed axonal‐demyelinating neuropathy. In Patients 12, 13, 14 and 15, no abnormalities were found. Laboratory findings In all patients with electrophysiological criteria for neuropathy the laboratory investigations as listed above were investigated. In none of the patients was evidence found for other causes for neuropathy. Case 3 declined duplication testing for hereditary motor sensory neuropathy type 1 (HMSN1A gene). In Case 2, laboratory investigations revealed slightly elevated levels of ANA, but ENA levels were in the normal range. Further investigations revealed no evidence of inflammatory or immune‐mediated diseases. In this case, a sural nerve biopsy was performed. Five of our patients underwent mutation analysis. One patient (Case 1) carried a nonsense mutation (C784T). In one additional patient, we found a loss of heterozygosity (LOH) in a vestibular schwannoma. Nerve biopsy findings The sural nerve of Case 2 comprised 10 nerve fascicles surrounded by a perineurium, which was focally increased in thickness. Some fascicles were moderately distended by endoneurial oedema. Very few myelinated and unmyelinated nerve fibres were preserved. Rare clusters of some regenerated nerve fibres were occasionally seen. Numerous bands of Büngner indicated preceding loss of myelinated and unmyelinated axons (Fig. 1A and B). In addition, there were either isolated pathological Schwann cells with sometimes abnormally large nuclei (Fig. 1E and F), or groups of abnormal Schwann cells arranged in small or larger complexes of multiple, flat, closely attached, interdigitating cell processes, surrounded by a basal lamina and separated by electron optically empty extracellular spaces, some of which contained collagen filaments (Fig. 1C and D). No axons were detected within these tumour cell complexes, which clearly differed in appearance from bands of Büngner and onion bulb formations. Some isolated Schwann cells with abnormally long or semicircular processes surrounding empty spaces with floccular material resembled pathological ones. However, usually the abnormal cells showed a tendency towards coherence and compact growth. The shape of the pathological nuclei varied considerably. Some were indented by cytoplasmic inclusions with dilated components of the endoplasmic reticulum (Fig. 1F). Comparison of the clinical, imaging and electrophysiological data The results are summarized in Table 1. There were three patients with electrophysiological evidence of neuropathy with no clinical abnormalities related to peripheral nerve lesions and four patients with a mild neuropathic syndrome. Only three patients showed a moderate or severe, and therefore striking, neuropathic syndrome. Overall, 10 patients showed cutaneous abnormalities related to NF2, but only eight patients showed skin tumours (subcutaneous schwannoma and ‘NF2 plaques’). Comparing the presence of cutaneous abnormalities related to NF2 and evidence for neuropathy, all eight patients with skin tumours showed electrophysiological evidence for neuropathy. In contrast, all but two patients with neuropathy showed NF2‐related skin tumours. The patient with demyelinating neuropathy showed no cutaneous abnormalities (Case 3). This patient, according to clinical and electrophysiological criteria, may well suffer from demyelinating hereditary motor sensory neuropathy. The second patient with neuropathy but without cutaneous abnormalities is Case 10. In this patient, by comparison, first symptoms related to NF2 became evident relatively late in life and until today only bilateral vestibular schwannomas, various meningiomas and one intramedullar tumour in the cervical spinal cord have been detected. In all patients with multiple (more than six) skin tumours, axonal neuropathy was documented. In both patients suffering from mixed axonal‐demyelinating neuropathy, less than six cutaneous abnormalities related to NF2 were found. In summary, this indicates that there is a possible relationship between the presence of skin tumours and peripheral neuropathy. Comparing peripheral nerve lesions to MRI of the spinal cord in Case 2, tumour masses on proximal nerve sections and roots can be responsible for sensory and motor peripheral symptoms. In Case 2, large tumour masses on sciatic nerve sections in the pelvic region could explain reduced sensory nerve action potential (SNAP) of sural nerves. However, on upper extremities, which also had evidence of polyneuropathy on examination, comparable MRI images were not found. Additionally, the neuropathic syndrome was the first clinical abnormality in this patient. Furthermore, a sural nerve biopsy was performed in this patient. In all other cases with documented intra‐ and/or extraforaminal schwannoma, these results do not explain the clinical findings. Only in Case 11 are isolated prolonged f‐wave latencies of the median and tibial nerve due to small schwannomas on the corresponding proximal nerve roots. Discussion We present systematic data on the occurrence of peripheral neuropathy in NF2. Clinical signs manifesting a peripheral neuropathy occurred in 46.7% of patients. Electrophysio logical examination revealed evidence of neuropathy in 66.7%. This frequency is higher than described so far. Previously, polyneuropathy was observed in one larger series in up to 6% of patients suffering from NF2. A possible reason for this discrepancy might be a patient selection bias. Our study was done in isolated patients subsequently recruited from our outpatient clinic. Usually, these patients are looking for medical care in the more advanced stages of disease. In accordance with this, all patients with neuropathy had severe NF2 according to previously published criteria, although a few had late onset (Evans et al., 1992c; Parry et al., 1994). In one patient, however, polyneuropathy developed years before symptoms related to NF2 became evident. Family investigations were not performed. However, in a mouse model describing conditional biallelic NF2 mutations, subclinical peripheral nerve involvement including Schwann cell hyperplasia and myelination defects was found at a high frequency (Giovannini et al., 2000). Clinical neuropathy findings in our patients varied from mild to severe neuropathic syndromes. Three patients showed electrophysiological evidence of neuropathy and no clinical signs of polyneuropathy. A mild neuropathic syndrome documented in four patients consisted of absent ankle jerks and slight symmetrical hypaesthesia. Absent or reduced deep tendon reflexes are known to be caused by affected extra‐ or intraspinal nerve roots in NF2 patients. Hypaesthesia can also result from intraspinal tumour masses (Evans et al., 1992a). In summary, seven of 10 patients with neuropathy showed no or mild clinical signs related to neuropathy, leading to the assumption that the lesion of the peripheral nerves might be subclinical or masked by signs related to damage of the CNS and nerve roots, respectively. On the other hand, two patients suffered from a moderate neuropathic syndrome with absent ankle jerks, symmetrical hypaesthesia and atrophy of distal muscles. In one female we observed a severe neuropathy. There have been few case reports describing patients with initial polyneuropathy, where later in life other NF2‐related symptoms developed. One young boy suffered from muscle wasting and progressive weakness since childhood. After the diagnosis of a hereditary motor and sensory neuropathy, various subcutaneous tumours developed. Electrophysio logical findings were consistent with an axonal type of neuropathy (Overweg‐Plandsoen et al., 1996). In our study there were seven patients with an axonal neuropathy type, two patients with a mixed axonal‐ demyelinating neuropathy type, and one patient fulfilled criteria for a demyelinating neuropathy (Ad Hoc Sub committee of the American Academy of Neurology AIDS Task Force, 1991). Predominant electrophysical signs of axonal damage were found in one patient with mixed polyneuropathy. Cases described in the literature are of axonal or mixed type neuropathies, and those with detailed electrophysiological data show a mainly axonal type of neuropathy (Bosch et al., 1981; Thomas et al., 1990; Overweg‐Plandsoen et al., 1996; Iwata et al., 1998). Further case reports document symptomatic focal amyotrophy without evidence of root or peripheral nerve tumours showing axonal damage (Trivedi et al., 2000). Peripheral nerve lesions in NF2 can result from tumour masses within the proximal nerve roots, or along the peripheral nerve (Grazzi et al., 1998). In our series there were some patients with multinodular tumours in the area of the conus and cauda equina, in the proximal nerve roots, or in the extramedullar affecting neighbouring nerve roots. Lesions described were possibly responsible for local abnormalities, as in Case 5, in which proximal nerve tumour led to amyotrophy of the unilateral thigh, or Case 2, with tumour masses along the sciatic nerve. However, abnormal nerve conduction velocities of the sensory nerves and reduced SNAPs and the distribution of neurogenic changes revealed by electrophysiological investigations clearly suggested that the lesions were at the peripheral nerve level in our patients. In clinical studies, evidence of skin tumours occurred between 32% and 68%, and skin tumours appeared to be of two or three different types (Kanter et al., 1980; Evans et al., 1992b; Parry et al., 1994). In our study, skin tumours due to NF2 were found in 10 of 15 patients (66.7%). One patient was not included in this calculation due to the presence of a histologically proven lipoma. Clinical differentiation between cutaneous tumour types as described in the literature was not systematically achieved (Evans et al., 1992b). We differentiated patients with more than six (multiple) and less than six cutaneous tumours. Interestingly, multiple dermal schwannoma tumours on the back were often situated in a paraspinal position corresponding to the region of the short spinal nerves. Others found that the most common location was the back, with no further details listed (Parry et al., 1994). Based on current knowledge of the origin of skin tumours, observations in mouse models and our present findings, we show that there is a relation between the presence of skin tumours and peripheral neuropathy: a peripheral neuropathy was found in all of our patients with cutaneous schwannoma, and most patients with neuropathy showed cutaneous lesion related to NF2. In the patient with a demyelinating type of neuropathy and one female with an axonal type of neuropathy, no cutaneous abnormalities were found. As described above, the latter only developed clinical signs related to NF2 later in life. In conclusion, polyneuropathy in NF2 was much more common than expected when electrophysiological methods were applied for examination. We noted an apparent correlation between disease duration and the development of skin tumours that were associated with peripheral nerve lesions. In accordance with previous histopathological data from case reports we found fibre loss, Schwann cell complexes and increased collagen. Previously, however, the Schwann cells complexes were described as somehow irregular ‘coreless onion bulbs’ (Thomas et al., 1990; Iwata et al., 1998). The most interesting finding in ultrastructural pathology in our biopsy, however, was the demonstration of ‘de‐differentiated’ Schwann cells, either isolated or in complexes. The multiple interdigitating cell processes are very well compatible with a malfunction of mutated merlin, since merlin supposedly acts as a membrane–cytoskeleton linker. During the preparation of this manuscript, Gijtenbeek and colleagues have published a report on a patient with NF2 and similar peripheral nerve pathology (Gijtenbeek et al., 2001). Based on these findings we hypothesize that the aetiology of this frequent peripheral neuropathy syndrome in NF2 is caused by: (i) compression effects of multiple tumourlets originating along the length of the peripheral nerves on adjacent nerve fibres; (ii) unknown local toxic or metabolic influences of the endoneurial pathological cells on adjacent nerve fibres, which requires further clarification; or (iii) the inability of these cells to adhere to/ensheath the axon. Open in new tabDownload slide Open in new tabDownload slide Fig. 1 (A–F) Light and electron micrographs of the sural nerve biopsy of Case 4. (A) Semi‐thin cross sections of two segments of nerve fascicles showing severe loss of myelinated nerve fibres with only two remaining fibres (arrowheads), numerous bands of Büngner at the site of degenerated nerve fibres, and circumscribed complexes of abnormal cells (arrows). The oedematous area in (B) comprises vacuolated cells and one unequivocal tumour cell with an abnormally large nucleus (arrowhead) adjacent to an inconspicuous capillary. Toluidine blue staining. Magnification: ×360. (C) Borderline (arrowheads) between pathological Schwann cells on the right and normal Schwann cells with (arrows) or without unmyelinated axons on the left. Collagen fibres are surrounding the normal Schwann cells individually whereas the pathological cells are coherent and arranged in a large complex of multiple, flat, interdigitating cells and cell processes that are surrounded by a basal lamina. Clusters of collagen fibrils are located between the abnormal cells. Magnification: ×1940. (D) Similar complex of abnormal Schwann cells as shown in (A), but focally separated from adjacent, pre‐existing unmyelinated nerve fibres (arrows) and bands of Büngner by several layers of basal laminae (arrowheads). Many spaces between the abnormal cells are filled with electron optically lucent or floccular mucoid material containing only rare collagen filaments. Magnification: ×4600. (E and F) Isolated tumour cells cut at the level of the nucleus with multiple indentations and flat processes at the periphery. Some of the cytoplasmic vacuoles are covered by a basal lamina (arrowheads), indicating their connection with the extracellular space. No axons are enclosed by the tumour cells. The severely enlarged (giant) nucleus in (F) shows several cytoplasmic invaginations with dilated components of the endoplasmic reticulum. (E) Magnification: ×6700. (F) Magnification: ×9100. Open in new tabDownload slide Open in new tabDownload slide Fig. 1 (A–F) Light and electron micrographs of the sural nerve biopsy of Case 4. (A) Semi‐thin cross sections of two segments of nerve fascicles showing severe loss of myelinated nerve fibres with only two remaining fibres (arrowheads), numerous bands of Büngner at the site of degenerated nerve fibres, and circumscribed complexes of abnormal cells (arrows). The oedematous area in (B) comprises vacuolated cells and one unequivocal tumour cell with an abnormally large nucleus (arrowhead) adjacent to an inconspicuous capillary. Toluidine blue staining. Magnification: ×360. (C) Borderline (arrowheads) between pathological Schwann cells on the right and normal Schwann cells with (arrows) or without unmyelinated axons on the left. Collagen fibres are surrounding the normal Schwann cells individually whereas the pathological cells are coherent and arranged in a large complex of multiple, flat, interdigitating cells and cell processes that are surrounded by a basal lamina. Clusters of collagen fibrils are located between the abnormal cells. Magnification: ×1940. (D) Similar complex of abnormal Schwann cells as shown in (A), but focally separated from adjacent, pre‐existing unmyelinated nerve fibres (arrows) and bands of Büngner by several layers of basal laminae (arrowheads). Many spaces between the abnormal cells are filled with electron optically lucent or floccular mucoid material containing only rare collagen filaments. Magnification: ×4600. (E and F) Isolated tumour cells cut at the level of the nucleus with multiple indentations and flat processes at the periphery. Some of the cytoplasmic vacuoles are covered by a basal lamina (arrowheads), indicating their connection with the extracellular space. No axons are enclosed by the tumour cells. The severely enlarged (giant) nucleus in (F) shows several cytoplasmic invaginations with dilated components of the endoplasmic reticulum. (E) Magnification: ×6700. (F) Magnification: ×9100. Table 1 Summary of clinical data, NF2‐related manifestations, present clinical neuropathic syndrome and electrophysiological classification of neuropathy in our NF2 patients Case Age (years) Age of onseta (years) Family history NF2 severity Cranial nerve schwannomas Meningiomas Spinal schwannomas Cutaneous schwannomas Peripheral neuropathy Electrophysiological classification of neuropathy 1 37 17 Neg Severe Bilateral N VIII + C2/C3; whole lumbar areab +++ Moderate Ax 2 28 14 Neg Severe Bilateral N VIII, N V +++ C2/C5c,b; cauda equina +++ Severe Ax 3 37 26 Neg Severe Bilateral N VIII, N V – C7, L1, L2, cauda equinad – Moderate Demy 4 56 30 Pose Severe Bilateral N VIII – C4, L3d; C6, C7f + Mild Ax 5 28 12 Posg Severe Bilateral N VIII, N V +++ C2/C5, C2‐Th2b, L5, S1d; L2, L3f; cauda equina +++ Mild Ax 6 27 19 Neg Severe Bilateral N VIII +++ Conus medullaris, cauda equina, L3/L4c + Mild Ax‐demy 7 39 14 Neg Severe Unilateral N IX Bilateral N VIII, N V +++ ND +++ Mild Ax 8 32 17 Neg Severe Bilateral N VIII, N V + C3/C4c; C3f +++ – Ax 9 31 18 Neg Severe Bilateral N VIII; Unilateral N V, N IV +++ C3/C4, C6/C7c; conus medullaris, cauda equinad,c,f + – Ax‐demy 10 48 44 Neg Severe Bilateral N VIII +++ C1/C2c,b – – Ax 11 37 20 Neg Severe Bilateral N VIII + C6, C7d,c; conus medullaris – – – 12 49 35 Neg Severe Bilateral N VIII +++ Hole cervical areaf; cauda equina – – – 13 30 26 Neg Severe Bilateral N VIII; Unilateral N V +++ C7, Th1f; conus medullaris – – – 14 57 34 Neg Mild Bilateral N VIII +++ None – – – 15 33 15 Neg Severe Bilateral N VIII – C4f; L4/S1c – – – Case Age (years) Age of onseta (years) Family history NF2 severity Cranial nerve schwannomas Meningiomas Spinal schwannomas Cutaneous schwannomas Peripheral neuropathy Electrophysiological classification of neuropathy 1 37 17 Neg Severe Bilateral N VIII + C2/C3; whole lumbar areab +++ Moderate Ax 2 28 14 Neg Severe Bilateral N VIII, N V +++ C2/C5c,b; cauda equina +++ Severe Ax 3 37 26 Neg Severe Bilateral N VIII, N V – C7, L1, L2, cauda equinad – Moderate Demy 4 56 30 Pose Severe Bilateral N VIII – C4, L3d; C6, C7f + Mild Ax 5 28 12 Posg Severe Bilateral N VIII, N V +++ C2/C5, C2‐Th2b, L5, S1d; L2, L3f; cauda equina +++ Mild Ax 6 27 19 Neg Severe Bilateral N VIII +++ Conus medullaris, cauda equina, L3/L4c + Mild Ax‐demy 7 39 14 Neg Severe Unilateral N IX Bilateral N VIII, N V +++ ND +++ Mild Ax 8 32 17 Neg Severe Bilateral N VIII, N V + C3/C4c; C3f +++ – Ax 9 31 18 Neg Severe Bilateral N VIII; Unilateral N V, N IV +++ C3/C4, C6/C7c; conus medullaris, cauda equinad,c,f + – Ax‐demy 10 48 44 Neg Severe Bilateral N VIII +++ C1/C2c,b – – Ax 11 37 20 Neg Severe Bilateral N VIII + C6, C7d,c; conus medullaris – – – 12 49 35 Neg Severe Bilateral N VIII +++ Hole cervical areaf; cauda equina – – – 13 30 26 Neg Severe Bilateral N VIII; Unilateral N V +++ C7, Th1f; conus medullaris – – – 14 57 34 Neg Mild Bilateral N VIII +++ None – – – 15 33 15 Neg Severe Bilateral N VIII – C4f; L4/S1c – – – aAge of onset of NF2 related symptoms; bintramedullar; cextramedullar; dintraforaminal; epatient’s son reported symptoms related to NF2; fextraspinal; gdisease was inherited from patient’s father. ND = not done; – = absent; + = one to five tumours; +++ = six or more tumours; Neg = negative; Pos = positive; N V = trigeminal nerve; N IV = trochlear nerve; N VIII = vestibular nerve; N IX = glossopharyngeal nerve; L = lumbar nerve root; C = cervical nerve root; Th = thoracic nerve root; S = sacral nerve root; Ax = axonal type of neuropathy; Demy = demyelinating type of neuropathy; Ax‐demy = mixed type of axonal–demyelinating neuropathy. Classification of neuropathic syndromes: mild = absent ankle jerks, slight symmetrical hypaesthesia; moderate = ‘mild’ plus atrophy of distal muscles or deformity of foot; severe = ‘moderate’ plus trophic disturbances, severe hypaesthesia and severe hypalgesia or analgesia. Open in new tab Table 1 Summary of clinical data, NF2‐related manifestations, present clinical neuropathic syndrome and electrophysiological classification of neuropathy in our NF2 patients Case Age (years) Age of onseta (years) Family history NF2 severity Cranial nerve schwannomas Meningiomas Spinal schwannomas Cutaneous schwannomas Peripheral neuropathy Electrophysiological classification of neuropathy 1 37 17 Neg Severe Bilateral N VIII + C2/C3; whole lumbar areab +++ Moderate Ax 2 28 14 Neg Severe Bilateral N VIII, N V +++ C2/C5c,b; cauda equina +++ Severe Ax 3 37 26 Neg Severe Bilateral N VIII, N V – C7, L1, L2, cauda equinad – Moderate Demy 4 56 30 Pose Severe Bilateral N VIII – C4, L3d; C6, C7f + Mild Ax 5 28 12 Posg Severe Bilateral N VIII, N V +++ C2/C5, C2‐Th2b, L5, S1d; L2, L3f; cauda equina +++ Mild Ax 6 27 19 Neg Severe Bilateral N VIII +++ Conus medullaris, cauda equina, L3/L4c + Mild Ax‐demy 7 39 14 Neg Severe Unilateral N IX Bilateral N VIII, N V +++ ND +++ Mild Ax 8 32 17 Neg Severe Bilateral N VIII, N V + C3/C4c; C3f +++ – Ax 9 31 18 Neg Severe Bilateral N VIII; Unilateral N V, N IV +++ C3/C4, C6/C7c; conus medullaris, cauda equinad,c,f + – Ax‐demy 10 48 44 Neg Severe Bilateral N VIII +++ C1/C2c,b – – Ax 11 37 20 Neg Severe Bilateral N VIII + C6, C7d,c; conus medullaris – – – 12 49 35 Neg Severe Bilateral N VIII +++ Hole cervical areaf; cauda equina – – – 13 30 26 Neg Severe Bilateral N VIII; Unilateral N V +++ C7, Th1f; conus medullaris – – – 14 57 34 Neg Mild Bilateral N VIII +++ None – – – 15 33 15 Neg Severe Bilateral N VIII – C4f; L4/S1c – – – Case Age (years) Age of onseta (years) Family history NF2 severity Cranial nerve schwannomas Meningiomas Spinal schwannomas Cutaneous schwannomas Peripheral neuropathy Electrophysiological classification of neuropathy 1 37 17 Neg Severe Bilateral N VIII + C2/C3; whole lumbar areab +++ Moderate Ax 2 28 14 Neg Severe Bilateral N VIII, N V +++ C2/C5c,b; cauda equina +++ Severe Ax 3 37 26 Neg Severe Bilateral N VIII, N V – C7, L1, L2, cauda equinad – Moderate Demy 4 56 30 Pose Severe Bilateral N VIII – C4, L3d; C6, C7f + Mild Ax 5 28 12 Posg Severe Bilateral N VIII, N V +++ C2/C5, C2‐Th2b, L5, S1d; L2, L3f; cauda equina +++ Mild Ax 6 27 19 Neg Severe Bilateral N VIII +++ Conus medullaris, cauda equina, L3/L4c + Mild Ax‐demy 7 39 14 Neg Severe Unilateral N IX Bilateral N VIII, N V +++ ND +++ Mild Ax 8 32 17 Neg Severe Bilateral N VIII, N V + C3/C4c; C3f +++ – Ax 9 31 18 Neg Severe Bilateral N VIII; Unilateral N V, N IV +++ C3/C4, C6/C7c; conus medullaris, cauda equinad,c,f + – Ax‐demy 10 48 44 Neg Severe Bilateral N VIII +++ C1/C2c,b – – Ax 11 37 20 Neg Severe Bilateral N VIII + C6, C7d,c; conus medullaris – – – 12 49 35 Neg Severe Bilateral N VIII +++ Hole cervical areaf; cauda equina – – – 13 30 26 Neg Severe Bilateral N VIII; Unilateral N V +++ C7, Th1f; conus medullaris – – – 14 57 34 Neg Mild Bilateral N VIII +++ None – – – 15 33 15 Neg Severe Bilateral N VIII – C4f; L4/S1c – – – aAge of onset of NF2 related symptoms; bintramedullar; cextramedullar; dintraforaminal; epatient’s son reported symptoms related to NF2; fextraspinal; gdisease was inherited from patient’s father. ND = not done; – = absent; + = one to five tumours; +++ = six or more tumours; Neg = negative; Pos = positive; N V = trigeminal nerve; N IV = trochlear nerve; N VIII = vestibular nerve; N IX = glossopharyngeal nerve; L = lumbar nerve root; C = cervical nerve root; Th = thoracic nerve root; S = sacral nerve root; Ax = axonal type of neuropathy; Demy = demyelinating type of neuropathy; Ax‐demy = mixed type of axonal–demyelinating neuropathy. Classification of neuropathic syndromes: mild = absent ankle jerks, slight symmetrical hypaesthesia; moderate = ‘mild’ plus atrophy of distal muscles or deformity of foot; severe = ‘moderate’ plus trophic disturbances, severe hypaesthesia and severe hypalgesia or analgesia. Open in new tab Table 2 Electrophysiological investigation of all patients Case Tibial nerve Median nerve Sural nerve Median nerve EMG DML [ms] (<5.1) CMAP [mV] (>5) NCV [ms] (>40.6) f‐wave latency [ms] DML [ms] (<4.2) CMAP [mV] (>5) NCV [ms] (>50) f‐wave latency [ms] SNAP [µV] (>6) NCV [ms] (>40.6) SNAP [µV] (>6.6) NCV [ms] (>46.9) 1 3.8 11.2 40 58.4 [<61] 3.1 17.5 63 29 [<31.5] 3.1 58 ND ND Neur 2 0 0 0 0 [<58] 6.4 3.9 49 NR [<30.5] 0 0 0 0 Neur 3 5 11.9 37.8 56.6 [<61] 3.9 22.4 61.4 29.4 [<31.5] 8.5 42 0 0 Neur 4 5.7 1.7 51.2 NR [<61] 2.9 18.1 54.9 NR [<31.5] 3 51.5 7.6 49 Neur 5 5.1 15 45 52 [<58] 4.4 15 53 27 [<30.5] 4 51 ND ND Neur 6 5.5 3.6 35 54.6 [<61] 4 6 56 29.4 [<31.5] 0 0 12 42 Norm 7 4 3 38.8 61 [<58] ND ND ND ND [<30.5] 3.5 49.7 ND ND ND 8 3.8 8.8 43.1 57 [<61] 3.2 14.4 66 26.4 [<31.5] 4.4 46.4 11.9 45 Norm 9 5.4 10 59 54 [<58] 4 17 51 32 [<30.5] 0 0 15 43 Norm 10 4.5 18 51 48 [<58] 4.1 5.2 44 NR [<30.5] 3 59 5.6 50 ND 11 3.9 14.5 52 60.8 [<61] 3.8 18.4 59 65.7 [<31.5] 11.5 46 7.4 42 Norm 12 3 25 50.4 48 [<58] 3.4 11.7 60 27 [<30.5] 21 44 27 51 Norm 13 4.7 22.1 48 47 [<61] 2.9 10 60 26 [<31.5] 6.4 52 9.9 55 Norm 14 3.3 22 52 48 [<58] 3.1 17 57 24 [<30.5] 16 60 28 54 Norm 15 3.7 12.7 45 45.2 [<61] 3 6.4 67.8 25 [<31.5] 12.9 48 13.9 49 ND Case Tibial nerve Median nerve Sural nerve Median nerve EMG DML [ms] (<5.1) CMAP [mV] (>5) NCV [ms] (>40.6) f‐wave latency [ms] DML [ms] (<4.2) CMAP [mV] (>5) NCV [ms] (>50) f‐wave latency [ms] SNAP [µV] (>6) NCV [ms] (>40.6) SNAP [µV] (>6.6) NCV [ms] (>46.9) 1 3.8 11.2 40 58.4 [<61] 3.1 17.5 63 29 [<31.5] 3.1 58 ND ND Neur 2 0 0 0 0 [<58] 6.4 3.9 49 NR [<30.5] 0 0 0 0 Neur 3 5 11.9 37.8 56.6 [<61] 3.9 22.4 61.4 29.4 [<31.5] 8.5 42 0 0 Neur 4 5.7 1.7 51.2 NR [<61] 2.9 18.1 54.9 NR [<31.5] 3 51.5 7.6 49 Neur 5 5.1 15 45 52 [<58] 4.4 15 53 27 [<30.5] 4 51 ND ND Neur 6 5.5 3.6 35 54.6 [<61] 4 6 56 29.4 [<31.5] 0 0 12 42 Norm 7 4 3 38.8 61 [<58] ND ND ND ND [<30.5] 3.5 49.7 ND ND ND 8 3.8 8.8 43.1 57 [<61] 3.2 14.4 66 26.4 [<31.5] 4.4 46.4 11.9 45 Norm 9 5.4 10 59 54 [<58] 4 17 51 32 [<30.5] 0 0 15 43 Norm 10 4.5 18 51 48 [<58] 4.1 5.2 44 NR [<30.5] 3 59 5.6 50 ND 11 3.9 14.5 52 60.8 [<61] 3.8 18.4 59 65.7 [<31.5] 11.5 46 7.4 42 Norm 12 3 25 50.4 48 [<58] 3.4 11.7 60 27 [<30.5] 21 44 27 51 Norm 13 4.7 22.1 48 47 [<61] 2.9 10 60 26 [<31.5] 6.4 52 9.9 55 Norm 14 3.3 22 52 48 [<58] 3.1 17 57 24 [<30.5] 16 60 28 54 Norm 15 3.7 12.7 45 45.2 [<61] 3 6.4 67.8 25 [<31.5] 12.9 48 13.9 49 ND CMAP = distal compound motor action potential; SNAP = sensory nerve action potential; NCV = nerve conduction velocity; DML=distal motor latency; 0 = no motor or sensory response; NR = non‐reproducible; ND = not done; Neur = neurogenic pattern; Norm = normal. Normal values are listed in parentheses below DML, CMAP, SNAP and NLG. Normal values were established in our laboratory according to published age‐matched, temperature and height corrected values (Ludin, 1993). In Case 1, axonal lesion was found because of a reduced SNAP of the sural nerve and neurogenic changes including spontaneous activity in EMG of the anterior tibialis muscle. The EMG of the gluteus medius muscle showed no abnormalities. In Case 2, no tibial nerve CMAP, no SNAP of the sural and median nerve were detected. EMG revealed neurogenic pattern and axonal polyneuropathy was diagnosed. Case 3 most likely suffered from demyelinating neuropathy. DML tibial nerve was in upper limit. NCV of the sural nerve was reduced and SNAP of the median nerve absent. EMG showed mild chronic neurogenic pattern. Case 4 suffered from axonal neuropathy because of prolonged DML, distinct reduced CMAP of the tibial nerve, reduced SNAP of the sural nerve and neurogenic pattern in EMG. Case 5 had an axonal neuropathy because of prolonged DML of the tibial nerve and of the median nerve, reduced SNAP of the sural nerve and neurogenic pattern in EMG. In Case 6, absent sural nerve SNAP, prolonged DML, reduced CMAP and reduced NCV of the tibial nerve, and reduced sensible NCV of the median nerve were documented leading to mixed axonal–demyelinating neuropathy with axonal component of demyelination. Case 8 showed reduced SNAP of the sural nerve. In Case 9 prolonged DML of the tibial nerve, absent sural nerve potential, prolonged f‐wave latency and reduced sensible NCV were documented. A mixed axonal–demyelinating neuropathy was supposed. Case 10 showed reduced SNAP of the sural nerve and median nerve, CMAP at lower limit of the median nerve and discrete reduced NCV of the median nerve. EMG was not done because of patients declining. An axonal lesion was documented. In Case 11, prolonged f‐wave latencies of the median and tibial nerve were documented. Open in new tab Table 2 Electrophysiological investigation of all patients Case Tibial nerve Median nerve Sural nerve Median nerve EMG DML [ms] (<5.1) CMAP [mV] (>5) NCV [ms] (>40.6) f‐wave latency [ms] DML [ms] (<4.2) CMAP [mV] (>5) NCV [ms] (>50) f‐wave latency [ms] SNAP [µV] (>6) NCV [ms] (>40.6) SNAP [µV] (>6.6) NCV [ms] (>46.9) 1 3.8 11.2 40 58.4 [<61] 3.1 17.5 63 29 [<31.5] 3.1 58 ND ND Neur 2 0 0 0 0 [<58] 6.4 3.9 49 NR [<30.5] 0 0 0 0 Neur 3 5 11.9 37.8 56.6 [<61] 3.9 22.4 61.4 29.4 [<31.5] 8.5 42 0 0 Neur 4 5.7 1.7 51.2 NR [<61] 2.9 18.1 54.9 NR [<31.5] 3 51.5 7.6 49 Neur 5 5.1 15 45 52 [<58] 4.4 15 53 27 [<30.5] 4 51 ND ND Neur 6 5.5 3.6 35 54.6 [<61] 4 6 56 29.4 [<31.5] 0 0 12 42 Norm 7 4 3 38.8 61 [<58] ND ND ND ND [<30.5] 3.5 49.7 ND ND ND 8 3.8 8.8 43.1 57 [<61] 3.2 14.4 66 26.4 [<31.5] 4.4 46.4 11.9 45 Norm 9 5.4 10 59 54 [<58] 4 17 51 32 [<30.5] 0 0 15 43 Norm 10 4.5 18 51 48 [<58] 4.1 5.2 44 NR [<30.5] 3 59 5.6 50 ND 11 3.9 14.5 52 60.8 [<61] 3.8 18.4 59 65.7 [<31.5] 11.5 46 7.4 42 Norm 12 3 25 50.4 48 [<58] 3.4 11.7 60 27 [<30.5] 21 44 27 51 Norm 13 4.7 22.1 48 47 [<61] 2.9 10 60 26 [<31.5] 6.4 52 9.9 55 Norm 14 3.3 22 52 48 [<58] 3.1 17 57 24 [<30.5] 16 60 28 54 Norm 15 3.7 12.7 45 45.2 [<61] 3 6.4 67.8 25 [<31.5] 12.9 48 13.9 49 ND Case Tibial nerve Median nerve Sural nerve Median nerve EMG DML [ms] (<5.1) CMAP [mV] (>5) NCV [ms] (>40.6) f‐wave latency [ms] DML [ms] (<4.2) CMAP [mV] (>5) NCV [ms] (>50) f‐wave latency [ms] SNAP [µV] (>6) NCV [ms] (>40.6) SNAP [µV] (>6.6) NCV [ms] (>46.9) 1 3.8 11.2 40 58.4 [<61] 3.1 17.5 63 29 [<31.5] 3.1 58 ND ND Neur 2 0 0 0 0 [<58] 6.4 3.9 49 NR [<30.5] 0 0 0 0 Neur 3 5 11.9 37.8 56.6 [<61] 3.9 22.4 61.4 29.4 [<31.5] 8.5 42 0 0 Neur 4 5.7 1.7 51.2 NR [<61] 2.9 18.1 54.9 NR [<31.5] 3 51.5 7.6 49 Neur 5 5.1 15 45 52 [<58] 4.4 15 53 27 [<30.5] 4 51 ND ND Neur 6 5.5 3.6 35 54.6 [<61] 4 6 56 29.4 [<31.5] 0 0 12 42 Norm 7 4 3 38.8 61 [<58] ND ND ND ND [<30.5] 3.5 49.7 ND ND ND 8 3.8 8.8 43.1 57 [<61] 3.2 14.4 66 26.4 [<31.5] 4.4 46.4 11.9 45 Norm 9 5.4 10 59 54 [<58] 4 17 51 32 [<30.5] 0 0 15 43 Norm 10 4.5 18 51 48 [<58] 4.1 5.2 44 NR [<30.5] 3 59 5.6 50 ND 11 3.9 14.5 52 60.8 [<61] 3.8 18.4 59 65.7 [<31.5] 11.5 46 7.4 42 Norm 12 3 25 50.4 48 [<58] 3.4 11.7 60 27 [<30.5] 21 44 27 51 Norm 13 4.7 22.1 48 47 [<61] 2.9 10 60 26 [<31.5] 6.4 52 9.9 55 Norm 14 3.3 22 52 48 [<58] 3.1 17 57 24 [<30.5] 16 60 28 54 Norm 15 3.7 12.7 45 45.2 [<61] 3 6.4 67.8 25 [<31.5] 12.9 48 13.9 49 ND CMAP = distal compound motor action potential; SNAP = sensory nerve action potential; NCV = nerve conduction velocity; DML=distal motor latency; 0 = no motor or sensory response; NR = non‐reproducible; ND = not done; Neur = neurogenic pattern; Norm = normal. Normal values are listed in parentheses below DML, CMAP, SNAP and NLG. Normal values were established in our laboratory according to published age‐matched, temperature and height corrected values (Ludin, 1993). In Case 1, axonal lesion was found because of a reduced SNAP of the sural nerve and neurogenic changes including spontaneous activity in EMG of the anterior tibialis muscle. The EMG of the gluteus medius muscle showed no abnormalities. In Case 2, no tibial nerve CMAP, no SNAP of the sural and median nerve were detected. EMG revealed neurogenic pattern and axonal polyneuropathy was diagnosed. Case 3 most likely suffered from demyelinating neuropathy. DML tibial nerve was in upper limit. NCV of the sural nerve was reduced and SNAP of the median nerve absent. EMG showed mild chronic neurogenic pattern. Case 4 suffered from axonal neuropathy because of prolonged DML, distinct reduced CMAP of the tibial nerve, reduced SNAP of the sural nerve and neurogenic pattern in EMG. Case 5 had an axonal neuropathy because of prolonged DML of the tibial nerve and of the median nerve, reduced SNAP of the sural nerve and neurogenic pattern in EMG. In Case 6, absent sural nerve SNAP, prolonged DML, reduced CMAP and reduced NCV of the tibial nerve, and reduced sensible NCV of the median nerve were documented leading to mixed axonal–demyelinating neuropathy with axonal component of demyelination. Case 8 showed reduced SNAP of the sural nerve. In Case 9 prolonged DML of the tibial nerve, absent sural nerve potential, prolonged f‐wave latency and reduced sensible NCV were documented. A mixed axonal–demyelinating neuropathy was supposed. Case 10 showed reduced SNAP of the sural nerve and median nerve, CMAP at lower limit of the median nerve and discrete reduced NCV of the median nerve. EMG was not done because of patients declining. An axonal lesion was documented. In Case 11, prolonged f‐wave latencies of the median and tibial nerve were documented. Open in new tab References Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Neurology 1991 ; 41 : 617 –8. Bosch EP, Murphy MJ, Cancilla PA. Peripheral neurofibromatosis and peroneal muscular atrophy. Neurology 1981 ; 31 : 1408 –14. Evans DG, Huson SM, Donnai D, Neary W, Blair V, Newton V, et al. A clinical study of type 2 neurofibromatosis. Q J Med 1992 a; 84 : 603 –18. Evans DG, Huson SM, Donnai D, Neary W, Blair V, Newton V, et al. A genetic study of type 2 neurofibromatosis in the United Kingdom. II. Guidelines for genetic counselling. J Med Genet 1992 b; 29 : 847 –52. Evans DG, Huson SM, Donnai D, Neary W, Blair V, Teare D, et al. A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity. J Med Genet 1992 c; 29 : 841 –6. Evans DG, Trueman L, Wallace A, Collins S, Strachan T. Genotype/phenotype correlations in type 2 neurofibromatosis (NF2): evidence for more severe disease associated with truncating mutations. J Med Genet 1998 ; 35 : 450 –5. Evans DG, Sainio M, Baser ME. Neurofibromatosis type 2. [Review]. J Med Genet 2000 ; 37 : 897 –904. Gijtenbeek JMM, Gabreels‐Festen AA, Lammens M, Zwarts MJ, van Engelen BG. Mononeuropathy multiplex as the initial manifestation of neurofibromatosis type 2. Neurology 2001 ; 56 : 1766 –8. Giovannini M, Robanus‐Maandag E, van der Valk M, Niwa‐Kawakita M, Abramowski V, Goutebroze L, et al. Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Genes Dev 2000 ; 14 : 1617 –30. Grazzi L, Chiapparini L, Parati EA, Giombini S, D’Amico D, Leone M, et al. Type II neurofibromatosis presenting as quadriceps atrophy. Ital J Neurol Sci 1998 ; 19 : 94 –6. Gutmann DH. Molecular insights into neurofibromatosis 2. [Review]. Neurobiol Dis 1997 ; 3 : 247 –61. Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, et al. The diagnostic evaluation and multidisciplinary managment of neurofibromatosis 1 and neurofibromatosis 2. [Review]. JAMA 1997 ; 278 : 51 –7. Gutmann DH, Geist RT, Xu HM, Kim JS, Saporito‐Irwin S. Defects in neurofibromatosis 2 protein function can arise at multiple levels. Hum Mol Genet 1998 ; 7 : 335 –45. Iwata A, Kunimoto M, Inoue K. Schwann cell proliferation as the cause of peripheral neuropathy in neurofibromatosis‐2. J Neurol Sci 1998 ; 156 : 201 –4. Kanter WR, Eldridge R, Fabricant R, Allen JC, Koerber T. Central neurofibromatosis with bilateral acoustic neuroma: genetic, clinical and biochemical distinctions from peripheral neurofibromatosis. Neurology 1980 ; 30 : 851 –9. Kilpatrick TJ, Hjorth RJ, Gonzales MF. A case of neurofibromatosis 2 presenting with a mononeuritis multiplex. J Neurol Neurosurg Psychiatry 1992 ; 55 : 391 –3. Kimura J. Electrodiagnosis in diseases of nerve and muscle: principles and practice. 2nd ed. Philadelphia: Davis; 1989 . Ludin HP. Praktische Elektromyographie. Stuttgart: Enke Verlag; 1993 . MacCollin M. Clinical aspects. In: Friedman JM, Gutmann DH, MacCollin M, Riccardi VM, editors. Neurofibromatosis. 3rd ed. Baltimore: Johns Hopkins University Press; 1999 . p. 299 –326. MacCollin M, Gusella J. Neurofibromatosis type 2. In: Vogelstein B. Neurofibromatosis type 2. New York: McGraw‐Hill; 1998 . p. 443 –53. Martuza RL, Eldridge R. Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). [Review]. New Engl J Med 1988 ; 318 : 684 –8. Mautner VF, Tatagiba M, Lindenau M, Funsterer C, Pulst SM, Baser ME, et al. Spinal tumors in patients with neurofibromatosis type 2: MR imaging study of frequency, multiplicity, and variety. AJR Am J Roentgenol 1995 ; 165 : 951 –5. Onishi A, Nada O. Ultrastructure of the onion bulb‐like lamellated structure observed in the sural nerve in a case of von Recklinghausen’s disease. Acta Neuropathol (Berl) 1972 ; 20 : 258 –63. Overweg‐Plandsoen WC, Brouwer‐Mladin R, Merel P, de Vries L, Bijlsma EK. Neurofibromatosis type 2 in an adolescent boy with polyneuropathy and a mutation in the NF2 gene. J Neurol 1996 ; 243 : 724 –6. Parry DM, Eldridge R, Kaiser‐Kupfer MI, Bouzas EA, Pikus A, Patronas N. Neurofibromatosis 2 (NF2): clinical characteristics of 63 affected individuals and clinical evidence for heterogeneity. Am J Med Genet 1994 ; 52 : 450 –61. Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, et al. Alteration in a new gene encoding a putative membrane‐organizing protein causes neurofibromatosis type 2. Nature 1993 ; 363 : 515 –21. Thomas PK, King RH, Chiang TR, Scaravilli F, Sharma AK, Downie AW. Neurofibromatous neuropathy. Muscle Nerve 1990 ; 13 : 93 –101. Trivedi R, Byrne J, Huson SM, Donaghy M. Focal amyotrophy in neurofibromatosis 2. J Neurol Neurosurg Psychiatry 2000 ; 69 : 257 –61. Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM, et al. A novel moesin‐, ezrin‐, radixin‐like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 1993 ; 72 : 791 –800.
TI - Occurrence and characterization of peripheral nerve involvement in neurofibromatosis type 2
JF - Brain
DO - 10.1093/brain/awf115
DA - 2002-05-01
UR - https://www.deepdyve.com/lp/oxford-university-press/occurrence-and-characterization-of-peripheral-nerve-involvement-in-MeGwz7KBC9
SP - 996
EP - 1004
VL - 125
IS - 5
DP - DeepDyve
ER -