Electrophysiological findings in neurofibromatosis type 1

Journal of the Neurological Sciences 306 (2011) 42–48

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Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s

Electrophysiological findings in neurofibromatosis type 1 Deniz Yerdelen a,⁎, Filiz Koc b, Murat Durdu c, Mehmet Karakas d a

Baskent University Faculty of Medicine, Department of Neurology,Turkey Cukurova University Faculty of Medicine, Department of Neurology,Turkey c Baskent University Faculty of Medicine, Department of Dermatology, Turkey d Cukurova University Faculty of Medicine, Department of Dermatology Turkey b

a r t i c l e

i n f o

Article history: Received 8 December 2010 Received in revised form 27 March 2011 Accepted 28 March 2011 Available online 17 April 2011 Keywords: Neurofibromatosis type 1 Electrophysiological findings

a b s t r a c t Neurofibromatosis type 1 (NF1) is a common, autosomal dominant neurocutaneous disorder in which any organ system, including the skin, skeleton and nervous system can be affected. In this study, we compared the electrophysiological and magnetic resonance imaging (MRI) findings in patients with NF1. Thirty-nine adolescent and adult patients (23 women and 16 men) diagnosed with NF1 with a mean age of 25.8± 10 years (10–56) were included in this study. We collected data in the form of the results of neurological examinations, multimodal evoked potentials (EPs; brainstem auditory evoked potentials, BAEPs; somatosensory evoked potentials, SEPs; and visual evoked potentials, VEPs), cerebral/orbital/spinal MRIs, and electroneuromyography (ENMG). Twenty (51.3%) patients showed abnormal VEPs, 14 (35.9%) showed abnormal SEPs, and six (15.4%) showed abnormal BAEPs. All evoked potentials were abnormal in four (10.3%) cases. These electrophysiological findings occurred primarily in the absence of any clinical sign related to the affected system. MRI revealed pathologic findings in 26 of 39 patients, and these were not always correlated with visual, auditory, or somatosensory pathway abnormalities. ENMG showed polyneuropathy in two of 33 patients who underwent ENMG. Our study showed that MRI and electrophysiological abnormalities may be found in most patients with NF1, even in the absence of associated clinical symptoms or signs. Electrophysiological testing is helpful for monitoring the subclinical involvement of the central and peripheral nervous systems in patients with NF1. © 2011 Elsevier B.V. All rights reserved.

1. Introduction Neurofibromatosis type 1 (NF1) is a common, autosomal dominant neurocutaneous disorder affecting approximately one in 4000 live births [1]. Any organ system, including the skin, skeleton, and nervous system can be affected. The most common features of NF1 are pigmentary abnormalities, such as café-au-lait macules, axillary/ inguinal freckling, iris hamartomas (Lisch nodules), and neurofibromas [2,3]. Tumors and malformations of the nervous system, deformities of the skull and skeleton, or pressure exerted by neurofibromas on the peripheral nerves, spinal nerve roots, and spinal cord may result in the neurological manifestations of NF1 [4]. Furthermore, instrumental investigations using magnetic resonance imaging (MRI) and electrophysiological tests such as visual evoked potentials (VEPs) and electroneurography may reveal abnormal findings in the absence of symptoms or clinical signs [4,5]. Multimodal evoked potentials (EPs) in patients with NF1 have been reported in only two studies. The first study was conducted by Ammendola et al. in a group of 21 children with NF1; they reported that most participants had compromised EPs in the ⁎ Corresponding author at: Baskent University Faculty of Medicine, Adana Teaching and Research Center, Department of Neurology, Dadaloğlu mah. 39 sok. Yüreğir-AdanaTurkey. Posta kodu: 01250, Turkey. Tel.: + 90 322 327 2727; fax: + 90 322 327 1274. E-mail address: [email protected] (D. Yerdelen). 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.03.048

absence of clinical signs of related sensory pathway pathology [5]. The second study was conducted by Margari et al. in three young patients; they reported the subclinical involvement of the central nervous system, as shown by MRI and EPs [6]. Despite a considerable range of complications related to peripheral nerve development and associated tumors in NF1, the prevalence of peripheral nerve involvement in NF1 is considered rather low, as described in large clinical studies and the few case studies of polyneuropathies associated with NF1 [4,7]. In this study, electrophysiological studies including multimodal EPs and electroneuromyography were performed, and associated MRI findings in the adolescent and adult patients with NF1 were discussed. 2. Material and methods Thirty-nine adolescent and adult patients (23 women and 16 men) diagnosed with NF1 at a mean age of 25.8±10 years (10–56) were included in this study and ethical approval was obtained for the study. Clinical diagnosis of NF1 was confirmed according to the diagnostic criteria of the National Institutes of Health Consensus Development Conference-Neurofibromatosis [8]. The patients received neurological examinations; tests of brainstem auditory evoked potentials (BAEPs), somatosensory evoked potentials (SEPs), and visual evoked potentials (VEP); cerebral/orbital/spinal MRIs; and electroneuromyography (ENMG).

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and the active electrode was located 2 cm posterior and 7 cm lateral of the vertex, contralateral to the stimulated nerve. During posterior tibial nerve stimulation, the reference electrode was located on the Fz area, and the active electrode was located 2 cm posterior to the vertex.

SEPs were obtained bilaterally by stimulating the median nerve at the level of the wrist and by stimulating the posterior tibial nerve at the level of the medial malleoli via surface electrodes. During median nerve stimulation, the reference electrode was located on the Fz area, Table 1 Neurological, MRI and electrophysiological findings of the study group. No Age Sex Neurological findings

Cerebral MRI

Spinal MRI

Orbital MRI

SEP

VEP

BAEP

ENMG

1 2

10 17

F F

MMR N

n.d. n.d.

n.d. n.d.

N N

N N

N N

n.d. n.d.

3

23

F

Facial deformation

n.d.

n.d.

N

N

N

n.d.

4

21

F

N

n.d.

N

N

ABNL N

n.d.

5

32

M

N

n.d.

n.d.

N

N

N

N

6 7 8

36 28 22

M F M

N N N

N Hyperintense foci in bilateral ocipital and parietal areas Hemiatrophy; hyperintense foci in the periventricular areas Hyperintense foci in the thalamus and periventricular areas Gliosis in the left frontal area; hyperintense foci in the thalamus Parietal hyperintense foci N N

n.d. n.d. n.d.

N N N

N N N N ABNL N

N N N

9

25

F

MR

N

N

N

N

N

10

28

F

N

ABNL N

N

11

19

M

N

Cerebral and cerebellar atrophy; hyperintense foci in the temporal and biparietal areas Hyperintense foci in the cerebellum and thalamus; cerebellar ectopy Hyperintense foci in the globus pallidus

N n.d. Unilateral optic glioma n.d.

ABNL N

N

12

16

M

N

N

N

13 14

17 17

F F

15

23

M

16

35

F

N

Hyperintense foci in the globus pallidus

Hamartomas in the intraspinal and paravertebral areas of T6-L1 levels n.d.

17 18

25 22

M M

Hyperintense foci in the basal ganglia Hyperintense foci in the basal ganglia

19

20

F

N Paraparesis, skeletal deformities MR

20 21 22 23 24 25 26 27 28 29

23 12 13 45 44 28 22 38 17 56

F M F M M F F M F M

Lenticulostriate collateral vessels in the basal ganglia and thalamus; hyperintense foci in the globus pallidus Cerebellar asymmetric enlargement N Hyperintense foci in the left globus pallidus N N N N Lipoma in the interpeduncular system N Hyperintense foci in the periventricular area

30

29

F

31

44

F

32

19

M

Unilateral decreased visual acuity N

33

20

F

Positional vertigo

34

18

F

N

35

20

F

36 37

32 26

M F

Unilateral decreased hearing N Positional vertigo

38 39

33 32

F M

N N

Hyperintense foci in the mesencephalon and thalamus N N N Parietal hyperintense foci; hemiatrophy in the right hemisphere MR, complex partial Hyperintense foci in the cerebellum, epilepsy, paraparesis mesencephalon, optic tracts and thalamus

MR N N N N N N N N Complex partial epilepsy N

n.d. n.d. n.d. N n.d.

N

n.d. Unilateral optic glioma n.d.

N N

ABNL ABNL ABNL N

n.d. Spinal hamartomas

Unilateral optic glioma N n.d.

n.d.

N

N

N

ABNL N N Demyelinized PNP N n.d.

N Spinal hamartomas N Discopathy n.d. n.d. n.d. n.d. n.d. n.d.

n.d. n.d. n.d. n.d. n.d. N n.d. n.d. n.d. n.d.

ABNL ABNL ABNL ABNL ABNL ABNL ABNL N N ABNL

N ABNL ABNL N ABNL ABNL N ABNL ABNL ABNL

ABNL N N N N N N N N ABNL

N N N N N N N N N N

n.d.

ABNL N

N

N

ABNL ABNL N

N

n.d.

Unilateral optic glioma n.d.

N

ABNL N

N

n.d.

n.d.

N

ABNL N

N

n.d.

n.d.

N

N

N

n.d.

n.d.

ABNL ABNL ABNL N

n.d. Spinal and paravertebral hamartomas

n.d. Diminution in the optic chiasma n.d. N

N N

N N ABNL N

N N

N N

N N ABNL N

N N

Hyperintense foci in the cerebellum, temporal n.d. and occipital areas and right thalamus N n.d. Hyperintense foci in the hypocampus, parahipocampal gyrus and thalamus Hyperintense foci in the cerebellum, mesencephalon, optic tracts, thalamus and temporal area Hyperintense foci in the thalamus, hypocampus and cerebellum Hyperintense foci in the periventricular and right acustic canal Gliotic focus in the corpus callosum Hyperintense foci in the right palatin fossa and left infratemporal fossa, triventricular hydrocephalus N N

Unilateral N optic glioma Unilateral optic N glioma n.d. N

n.d. n.d.

N N ABNL N

N n.d.

ABNL ABNL ABNL Axonal PNP

N N ABNL N

N

MRI, magnetic resonance imaging; SEP, somatosensory evoked potentials; VEP, visual evoked potentials; BAEP, brainstem auditory evoked potentials; ENMG, electroneuromyography; F, female; M, male; N, normal; ABNL, abnormal findings; n.d., not done; MMR, mental motor retardation; MR, mental retardation and PNP, polyneuropathy.

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D. Yerdelen et al. / Journal of the Neurological Sciences 306 (2011) 42–48

The stimulus frequency was 2 Hz. Median and tibial nerves were stimulated with pulses of 0.1 ms and 0.2 ms duration, consecutively. Two sets of an average of 400 artifact-free responses were averaged for every extremity. Peak latencies and amplitudes of N19 and P22, obtained by stimulating the median nerve, and the peak latency and amplitude of P37, obtained by stimulating the posterior tibial nerve, were selected for measurement. VEPs were recorded using a black-and-white checkerboard displayed on a television screen that reversed the image each second. Each check subtended 37° of the visual field, and the contrast was 50%. The screen was placed 1 m from the nasion. Recordings of monocular fulfilled stimulation with an active scalp electrode on Oz referenced to Cz were obtained in a dark room. The ground electrode was placed around the forearm. An examiner watched the subjects during VEP recordings to ensure their focus on the television screen. The frequency limits were set at 2–100 Hz, and the time for analysis was 500 ms. A total of 400 responses was averaged for each eye. The latency and the peak amplitude values of the P100 components were taken into consideration. For BAEPs, the active electrode used in the BAEPs was located ipsilateral to the mastoid and the reference electrode was located on the vertex. BAEPs were obtained in response to clicks, with pulses lasting 0.1 ms delivered at a rate of 10 per second. The intensity of the clicks was 90 dB, and the contralateral ear was masked with a 40-dB noise. At least two trials, each of which consisted of 2000 single responses, were averaged by means of a 100 Hz–3 kHz band-pass filter. The analysis time was 20 ms. The absolute latency of I, III, and V responses were taken into consideration. During ENMG examination, subjects experienced a polyneuropathy protocol, which consisted of electrophysiological recordings with a surface electrode of two motor and sensory nerves (n. medianus and n. ulnaris) in the upper extremities and two motor nerves (n. tibialis posterior and n. peroneus) and one sensory nerve (n. suralis) in the

lower extremities. The needle EMG examined two proximal and two distal muscles of the upper and lower extremities. The results of the ENMG and EPs obtained from patients were compared with those of age- and height-matched healthy subjects. We used our laboratory controls, which were also compatible with the control values reported in the literature [9–11]. Cerebral, spinal, and orbital MRI examinations were performed using a 1.5-T MR apparatus (Siemens, Vision, Erlangen, Germany). 3. Results The neurological data obtained from two patients (one with mental retardation and one with paraparesis) showed complex partial seizures. One patient showed mental–motor retardation, three showed mental retardation, one showed facial deformation, one showed paraparesis and skeletal deformities, two showed positional vertigo, one had unilateral decreased hearing, and one had unilateral decreased visual acuity (Table 1). All patients received EP testing. Twenty (51.3%) patients showed abnormal VEPs, 14 (35.9%) showed abnormal SEPs, and six (15.4%) showed abnormal BAEPs. Twenty-six (66.7%) patients had at least one EP abnormality. All EPs were abnormal in four (10.3%) cases. The VEP data demonstrated that 17 patients had bilateral increased latency of the P100 wave, two patients had a unilateral bifid wave, and a unilateral VEP response could not be elicited in one patient. Four patients had bilateral increased latency in both the median and tibial SEPs. Five patients had bilateral increased latency in the tibial SEP. Two patients demonstrated deformed tibial SEPs (very low amplitude), and the tibial SEPs of two participants showed a deformed response on one side and increased latency on one side. One patient had one side with a deformed response evident in the median SEPs and one side with deformed response evident in the tibial SEPs. Six patients showed increased latency of 3 or more in I, III, V, I–III, and III–V responses in the BAEPs.

Table 2 Neurofibromatosis type 1 patients with pathologic evoked potentials. Only pathologic data are given. SEPs

VEPs

N19 L Normals Patients 4 8 10 11 14 15 16 17 18 20 21 22 23 24 25 26 27 28 29 30 31 32 33 35 37 39

p37 R

18.9 ± 1

L

BAEPs

P100 R

L

36.3 ± 2.4

102.3 ± 8 117 132 122 126 116 126 134

22.3 20.3

21.7 23.1

52.1 49.6

49.6 49.6

25.9

27.1 DR

52.1 DR DR DR 40 DR 43,2 DR

49.8

I R

L 1.7 ± 0.15

119 128 118 119 120 122 121

22

61 DR 42.4

41.2

L

V R

3.9 ± 0.19

2.1 2.2

22

III R

L 5.7 ± 0.25

4,3 4.4 4.4

125 119

45,4 45 41 DR

59 DR 42.4

DR

L

III–V R

2.1 ± 0.15

6.5 6.8 6.8 6.1

DR

I–III R

L

R

1.9 ± 0.18

2.2 2.8 4.4

4.4 2.4 2.4

6.5

2.2

2.4

130 123 AR DR

117 143 125

116 161 115

114 115 119 116 118

DR 116 118 115 117 120

6.1

2.42

6.6

2.4

2.5

2.2

2.8

SEPs, somatosensory evoked potentials; VEPs, visual evoked potentials; BAEPs, brainstem auditory evoked potentials; L, left; R, right; DR, deformed response (bifid wave or very low amplitude) and AR, absent response.

D. Yerdelen et al. / Journal of the Neurological Sciences 306 (2011) 42–48

All patients received cerebral MRI: 23 had hyperintense T2weighted foci, one had a lipoma, one had a gliotic focus in the corpus callosum, and one had cerebellar asymmetric enlargement. One of the patients who had hyperintense T2-weighted foci also had triventricular hydrocephalus. Thirteen patients had orbital MRIs, six of whom had optic gliomas and one of whom had diminution in the optic chiasma. Spinal MRIs were performed on 12 patients and four of 12 had hyperintense T2-weighted foci (Tables 1 and 2). Patients who did not receive spinal and orbital MRIs did not give approval for these tests. Our sixteenth patient showed no symptoms or clinical findings. However, the cerebral MRI revealed hyperintense T2-weighted foci (Fig. 1 a, b, c and d), the SEPs showed increased latency both by stimulating the median nerve at the wrist and by stimulating the posterior tibial nerve at the medial malleoli (Fig. 2 a and b), the P100 latency in the VEPs was increased bilaterally (Fig. 3), and BAEPs showed increased latency in all waves except the first one on the left (Fig. 4) (Tables 1 and 2). This patient exemplified subclinical cerebral involvement as well as the involvement of visual, brainstem, and somatosensory pathways. ENMG was performed on 33 patients. Six of the patients did not give approval for the ENMG. Results were normal, with the exception of those for two patients (Table 1). The fifteenth patient had severe

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motor axonal polyneuropathy. The needle EMG revealed chronic neurogenic changes in large-motor-unit action potentials, with decreased recruitment and few positive fibrillation potentials and positive sharp waves in the abductor pollicis brevis, abductor digiti minimus, and gastrocnemius muscles. The eighteenth patient had severe sensorimotor demyelinating polyneuropathy. Investigation with electromyography revealed chronic neurogenic changes with decreased recruitment, but no spontaneous activity. With the exception of Case 18, the patients did not manifest any other diseases that might have affected the results of nerve-conduction studies or multimodal EPs. Case 18, who showed polyneuropathy, was found to have Charcot–Marie–Tooth type 1A. 4. Discussion This study used MRI and electrophysiological tests to reveal the involvement of certain systems in most patients with NF1, although these patients did not have associated symptoms or clinical findings as had been reported in previous studies [5,6]. VEP pathology was the most frequent (51.3%) abnormal electrophysiological finding, which was consistent with the results of the study conducted by Ammendola et al. [5]. In our study, the orbital MRI revealed optic gliomas in five participants and diminution in the optic

Fig. 1. a, b and c: axial FLAIR and T2-weighted images showed hyperintense T2-weighted foci in bilateral hippocampus, parahippocampus and thalamus.d: Coronal post gadolinium spine echo T1-weighted image showed no enhancement in the lesions.

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Fig. 2. a and b: SEPs showed increased latency both by stimulating the median nerve at the wrist and by stimulating the posterior tibial nerve at the medial malleoli.

chiasma in one patient, and the cerebral MRI revealed hyperintense T2-weighted foci in the optical tracts of two of 20 patients with VEP pathology. Only one patient with abnormal VEPs had unilateral decreased visual acuity and optic glioma. Three patients with abnormal VEPs showed normal orbital MRIs. The cerebral MRIs were also normal in two of these three patients. In one of these three patients, hyperintense T2-weighted foci in the thalamus and periventricular areas were noted, which were irrelevant to the VEP results. These findings suggested that VEP is more sensitive than neuroimaging in terms of providing information about the involvement of the visual system and optic glioma during the early stage. The presence of electrophysiological abnormalities in the absence of optic system and brain lesions has been explained by the possible primary abnormality of visual processes in NF1. Incomplete, delayed, or abnormal myelinization of the visual pathway has been suggested to explain

these findings [12]. Many studies have reported VEP to be a sensitive and cost-effective screening test for optic nerve gliomas in children [13]. In 14 (35.9%) of our patients, SEPs were pathological, and seven of 14 had MRI lesions. Abnormal findings were elicited, especially by stimulating the posterior tibial nerves. Only one SEP study has been conducted in children with NF1, and their pathology ratio was 14.2% [5]. Our pathologic SEP ratio was remarkable. Six (15.4%) of our patients demonstrated pathologic BAEPs, and all of these also had pathologic MRI. One of these patients demonstrated decreased hearing on the same side as the BAEP pathology. Neurootologic studies in patients with NF1 are scarce, so the prevalence of neuro-otologic abnormalities is not clearly known. Two studies have reported abnormal findings in auditory brainstem responses at rates of 28.5% and 27%. However, these findings were not correlated with

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Fig. 3. P100 latency in VEPs was increased bilaterally.

MRI findings [5,14]. Our results suggest a correlation between BAEPs and MRI findings. These EPs abnormalities are not specific to NF1. Similiar changes may be encountered in many diseases that can affect the visual, auditory, and somatosensory pathways, including multiple sclerosis and neuro-Behçet [15,16]. Although the findings are not very specific, our data and those of other studies indicate that multimodal EPs may elicit the pathology in one or more sensory pathways in patients with normal encephalic MRIs. Because MRI explores the brain morphologically, and EPs analyze the functions of sensorial pathways, EPs may emphasize functional abnormalities that are not yet evident anatomically and, therefore, cannot create observable MRI alterations [5]. The MRI pathology ratio was 66.7% in our study. Consistent with our findings, Ammendola et al. reported that MRI abnormalities are the

most frequent abnormality [5]. MRI lesions characterized by hyperintense T2-weighted foci are generally asymptomatic and have been described as benign asymptomatic bright lesions such as dysmyelinization, hamartoma, heterotopy, or dysplasia by many authors [17–19]. As mentioned above, twenty-six (66.7%) patients of our case study had at least one EP abnormality. It is interesting that the MRI pathology ratio was also 66.7% in our study. We propose that the same percentage of patients with at least one EP abnormality and with MRI pathology in this study emphasizes the importance of multimodal EPs study in NF1. We documented motor polyneuropathy with axonal degeneration in one patient and sensorimotor demyelinating polyneuropathy in another patient of the 33 who underwent ENMG (6%). Neurofibromatous neuropathy in NF1 has been rarely reported and is characterized by a distal sensorimotor neuropathy associated with diffuse neurofibromatous

Fig. 4. BAEPs showed increased latency of all the waves except the first one on the left.

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changes in thickened peripheral nerves. Two different studies have reported that the frequency of neuropathy in NF1 was 2.3% and 1.3%, respectively [4,7]. Our fifteenth patient showed no other risk factors for neuropathy. Case 18, who suffered from polyneuropathy, was found to have Charcot–Marie–Tooth type 1A. The simultaneous occurrence of neurofibromatosis and a peripheral neuropathy that has the clinical and electrophysiological features of CMT1A disease has rarely been reported. Roos et al. reported a patient who simultaneously manifested NF1 and CMT1A and noted a possible genetic relationship between these two disorders [20]. On the other hand, Luspski et al. presented two patients with CMT1A and NF1 and concluded that the two diseases may have been independent of each other, and their cooccurrence a result of chance [21]. Case 18 in the present study, who had CMT1A and NF1 that were already reported, could not be used to establish a definite genetic relationship between these two diseases, but we suggest that underlying genetic events may have caused the observed pathology [22]. NF1 is characterized by multisystemic manifestations related, in part, to the accumulation of neurofibromas. Neurofibromas arise from the proliferation of Schwann cells and perineural fibroblasts in nerve and cutaneous nerve endings [7]. In this interesting disease, neurofibromas may present in the nervous system or in other organs along with clinical findings or in the absence of any significant clinical symptoms. Different studies have reported the involvement of different systems (peripheral nervous system, visual–brainstem–somatosensory pathways, heart, and abdomen) [5,7,23,24]. No study has discussed the underlying pathophysiology of the simultaneous involvement of different systems. Why some abnormalities become symptomatic, whereas others remain clinically unobservable remains unknown, but it has been suggested that morbidity associated with neurofibromas is dependent on the location of the lesions. Our study is the largest comprising multimodal EPs in adult and adolescent patients with NF1. Our findings showed that patients with NF1 could have morphological and/or functional brain abnormalities and peripheral nervous system involvement, even in the absence of clinical symptoms or findings. These electrophysiological methods may help us to understand the underlying pathology of NF1 and to reveal the clinical and subclinical central or peripheral nervous system involvement during the follow up of these patients. Our findings of subclinical abnormalities suggest the possible benefit of monitoring and collecting additional information on the natural history of NF1. Results that are currently described as subclinical abnormalities may be explained in the future with more sophisticated imaging and investigational methods combined with multimodal EPs in a larger sample of individuals with NF1.

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