Journal of Neurology

, Volume 260, Issue 1, pp 38–46 | Cite as

Accumulation of non-compressive fascicular lesions underlies NF2 polyneuropathy

  • P. Bäumer
  • V. F. Mautner
  • T. Bäumer
  • M. U. Schuhmann
  • M. Tatagiba
  • S. Heiland
  • T. Kaestel
  • M. Bendszus
  • M. Pham
Original Communication

Abstract

A distinct polyneuropathy (PNP) syndrome affects up to 66 % of patients with neurofibromatosis II (NF2). Whether this is primarily a diffuse PNP or due to single, surgically amenable mass lesions has not yet been conclusively demonstrated. We aimed to solve this question by investigating the pathomorphological MR imaging correlate of this rare disorder. Eight patients with NF2-PNP were characterized by clinical examination, electrophysiological studies, and genetic analysis. All patients additionally underwent extended peripheral nerve imaging by a novel protocol of large-coverage high-resolution MRI. Quantitative analyses were performed by separately evaluating cross-sectional images, and by categorizing lesions into non-compressive fascicular microlesions (<2 mm), intermediate lesions (2–5 mm), and compressive macrolesions (>5 mm). The predominant imaging findings were non-compressive fascicular microlesions and intermediate lesions. Proximal-to-distal cumulative lesion burden of these lesions correlated strongly with the severity of clinical symptoms of NF2-PNP. In contrast, compressive macrolesions were not found at all in several symptomatic extremities. We conclude that proximal-to-distal accumulation of non-compressive fascicular lesions instead of compressive mass lesions predominantly underlies the clinical manifestation and severity of NF2-associated PNP. Diagnostic management may now be assisted by large-coverage high-resolution imaging of plexus and peripheral nerves. Additionally, the results underscore the feasibility of this new method, which may open up new diagnostic and investigative possibilities for other disseminated disorders of the peripheral nervous system.

Keywords

Neurofibromatosis 2 Polyneuropathy Magnetic resonance imaging MR neurography 

Introduction

Neurofibromatosis 2 (NF2) is an autosomal dominant hereditary disorder characterized by the predisposition to develop slowly growing tumors in the central and peripheral nervous system. Half of the cases are hereditary while the other half arise from de novo mutations in the NF2 gene located on chromosome 22 [1]. The genetic defect in NF2 is a loss of function of the protein merlin, a cytoskeleton-associated protein that serves as a tumor suppressor. The distinctive clinical feature of the disease is the occurence of bilateral vestibular nerve schwannomas in 95 % of affected individuals, with other diagnostic criteria being the occurrence of meningiomas, gliomas, juvenile cataract, and schwannomas of other cranial or peripheral nerves [2, 3, 4, 5].

The life-long burden of severe morbidity associated with NF2 is considered to be mainly a consequence of the compressive effects of these CNS and PNS mass lesions. Hence, surgical reduction of tumor mass to prevent compressive organ damage and loss of function is the mainstay of treatment in NF2. In addition to the predominant CNS involvement, substantial morbidity can be attributed to a distinct peripheral polyneuropathy (PNP) syndrome associated with NF2 (NF2-PNP) [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16]. Most of the published reports describe NF2-PNP to be a symmetrical sensorimotor polyneuropathy with the predominant electrophysiological finding of axonal loss. Individual cases with predominant conduction slowing, indicating demyelination rather than axonal degeneration, are occasionally reported within these studied groups [14, 15]. Also, asymmetrical distribution with focal amyotrophy or a mononeuropathy multiplex pattern can be found in the literature [14, 15, 16, 17]. The largest studied series to date comprised 15 patients, of which seven (47 %) showed clinical signs of peripheral neuropathy while electrophysiological evidence was found in ten (67 %) [14].

It is well known that large compressive tumorous lesions, mostly peripheral nerve schwannomas, may cause symptoms of neuropathy in NF2 [18]. However, the anatomical sites at which tumorous mass lesions of the PNS are observed in individual patients often cannot explain the distribution of their clinical symptoms, and hence the full clinical pattern of the NF2-associated PNP syndrome [14, 19]. This marked discrepancy between the extent and number of peripheral nerve tumors and the clinical extent of peripheral neuropathy has led to the notion that NF2-PNP may occur independently of focal compressive nerve tumors. So far, no comprehensive imaging or histological post-mortem study has assessed the spatial distribution of nerve lesions and thereby attempted to prove pathomorphological correlates of NF2-PNP in the absence of compressive lesions along peripheral nerves. Further, only a handful of biopsy reports have been published with heterogeneous finding, so that structural correlates and pathomechanisms contributing to the manifestation and severity of NF2-PNP remain poorly understood.

Microstructural peripheral nerve MRI as employed here by high-resolution T2 sampling allows for precise lesion localization and quantification of peripheral nerve pathomorphology at the fascicular level [20, 21, 22, 23, 24, 25]. This imaging method has never been employed in NF2-PNP and may reveal nerve lesion patterns linked to the manifestation and clinical severity of NF2-PNP. The aim of this study was to characterize the pathomorphological imaging correlate of NF2-PNP and to investigate the hypothesis that NF2-PNP may be mainly ascribed to cumulative burden of smaller lesions rather than to compressive mass lesions.

Patients and methods

Clinical and demographic patient data

Physical examination

The study was approved by the institutional ethics committee (S-057/2009), and written informed consent was obtained from all participants. Eight patients with confirmed NF2 were recruited between 12/2009 and 12/2010 (Section for Phacomatoses, Hamburg-Eppendorf, Germany). All patients fulfilled the modified NIH criteria for definite NF2 [2] and underwent detailed physical neurological examinations of peripheral nerve sensory, motor and autonomic function by a single board-certified examiner (VFM, neurologist) with more than 20 years of experience in the diagnosis and treatment of NF2. Metabolic disorders (as alcoholism, diabetes, vitamin deficiencies), infectious diseases (as HIV/AIDS, Epstein-Barr, hepatitis C, Lyme disease, shingles), autoimmune disorders, kidney and liver diseases, hypothyroidism, and a history of exposure to poisons were excluded in all patients as potential risk factors for polyneuropathy unrelated to NF2.

Molecular genetic analysis

Genetic analyses determined the mutations in the NF2 tumor suppressor gene on chromosome 22q12. Direct sequencing of exons 1–15 of the NF2 gene was performed from blood DNA of peripheral leucocytes. Detection of genetic alterations was performed by multiple ligation-dependent probe amplification.

Nerve conduction studies and electromyography

Nerve conduction studies (NCS) and electromyography (EMG) studies were conducted by a single board-certified examiner (TB, neurologist) with 15 years of experience in the diagnosis and treatment of neuromuscular disease and peripheral neuropathies including NF2-PNP. Motor NCS included measurement of compound muscle action potential (CMAP), distal motor latencies (DML), conduction velocities in the lower leg, F-wave latencies, and presence of the tibial and peroneal nerve of both sides. Sensory NCS of both sural nerves included the amplitude of compound sensory nerve action potential, and conduction velocity (antidrome technique/surface electrodes). The performance of needle electromyography of selected muscles was guided by clinical suspicion of muscle involvement.

Classification of clinical severity of NF2-PNP

NF2 may be divided into two phenotypic subtypes according to disease onset and severity [26, 27]. All eight patients were classified into either “early onset NF2” or “late-onset NF2” in analogy to the Wishard and Feiling/Gardner phenotype according to the following criteria: Early onset: age of onset ≤20 years, multiple cerebral and spinal tumors. Late onset: age of onset ≥20 years, one cerebral tumor beside bilateral vestibular nerve schwannomas, ≤2 spinal tumors. The presence and the severity of NF2-PNP have yet to be incorporated into clinical classification schemes for the diagnostic determination and phenotypical severity grading of NF2. We stratified NF2-PNP into “subclinical”, “moderate”, and “severe” according to the following criteria:

“Subclinical” NF2-PNP was determined if only NCS and EMG evidence of axonal loss and/or demyelination was noted in the distribution of at least two peripheral nerves. “Moderate” NF2-PNP was determined if absent ankle jerks, slight symmetrical hypesthesia, and paresis of distal muscle groups (MRC grade 4) was noted in addition to electrophysiological signs of PNP. “Severe” NF2-PNP was determined if, additionally, physical findings indicated severe motor weakness (MRC Grade ≤ 3), atrophy of muscles, deformities of hands or feet, analgesia and loss of sensory modalities in the distribution of at least two peripheral nerves.

MRI examinations

MRI examinations were carried out on a 3-Tesla MRI scanner (Magnetom VERIO, Siemens AG, Erlangen, Germany). Contiguous coverage of both upper and/or both lower extremities was achieved by employing an array of various fat-saturated T2-weighted high-resolution sequences.

Large-coverage microstructural T2 sampling: paraspinal level to ankle region

In six (patients 1–6) of eight patients, clinical or electrophysiological evidence demonstrated a predominant focus of NF2-PNP at the lower extremities. These six patients underwent comprehensive MRI examination with microstructural (resolution 0.273 × 0.273 mm in most sequences) fascicular T2 sampling of the PNS. Lumbosacral plexus structures were covered by a 3D T2-w SPACE STIR (voxel size 0.95 × 0.95 × 1.0 mm, TR/TE/TI 3800/266/180) and gluteal regions by a transversal 2D T2-w fat-saturated TSE (voxel size 0.625 × 0625 × 4.0 mm, TR/TE 3000/50) with a 2 × 6 channel flexible body surface array coil and 12 channel spine array. Thigh, knee, lower legs, and ankle regions were covered on both sides using an eight-channel T/R quadrature birdcage extremity coil and a transversal T2-w fat-saturated TSE (voxel size 0.273 × 0.273 × 3.5 mm, TR/TE 7552/52). Contiguous coverage resulted in a total of 11 sequences with a total acquisition time of 75:35 min.

Large-coverage microstructural T2 sampling: upper extremities

Additionally, three (patients 1, 7, 8) of eight patients exhibited both clinical symptoms and signs on NCS/EMG studies of upper extremity peripheral neuropathy. These patients underwent a comprehensive MRN imaging examination with large-coverage and microstructural (resolution 0.254 × 0.254 mm in all but one sequence) T2 sampling of the PNS of the upper extremities. Analogous to the lower extremities, upper extremities were examined using a coronal TIRM (voxel size 0.844 × 0.844 × 3.0 mm, TR/TE/TI 5100/49/200) for the brachial plexus and a transversal T2-w fat-saturated TSE (voxel size 0.254 × 0.254 × 3.0 mm, TR/TE 6980/52) for upper arms, elbows, forearms, and wrists on both sides. Coverage of both extremities resulted in a total acquisition time of 64:55 min.

Image analysis

The evaluation of MR images was performed by two neuroradiologists (PB, MP) blinded to all patient data, each with more than 3 years of training in peripheral nerve MR imaging.

As pathomorphological imaging endpoints, the nerve T2 signal lesions were evaluated on the level of the nerve fascicle as the functionally meaningful first-order subunit of the nerve within the range of structural resolution. Separate nerves were assessed separately when appearing on the same slice (e.g., different plexus elements, or the tibial and peroneal nerve).

Quantitative analysis was performed from the lumbosacral plexus to the ankle in patients 1–6. Images were ordered and referenced according to their proximal-to-distal position with respect to the following three anatomical landmarks: the infrapiriform foramen, the knee joint space and the upper ankle joint space.

Fascicular T2 lesions were classified by size into the following categories:
  1. (I)

    “non-compressive microlesion” if the largest cross-sectional diameter of the lesion measured <2 mm.

     
  2. (II)

    “intermediate lesion” if the largest diameter of the lesion was ≥2 mm but <5 mm.

     
  3. (III)

    “compressive macrolesion” if the largest diameter of the lesion was ≥5 mm.

     
All lesions of type (II) and (III) were counted individually. The non-compressive microlesions of type (I) occurred with exceeding frequency, impeding exact lesion counts. In order to evaluate type (I) non-compressive lesions in a quantitative manner, the extent of fascicular involvement with type (I) lesions was operationalized into the following four-level ordinal scale of severity (evaluated slice-by-slice).
  • “0” normal appearance of all nerve fascicles in terms of fascicular T2 signal and caliber.

  • “1” fascicular T2 lesions with involvement of <25 % of fascicles.

  • “2” fascicular T2 lesions with involvement of ≥25 but <75 % of fascicles.

  • “3” fascicular T2 lesions with involvement of ≥75 % of fascicles traversing the respective cross section.

Affection by microlesions (type I) was evaluated slice-by-slice from proximal to distal and the cumulative score of overall fascicular involvement calculated. Cumulative frequency plots were used to describe lesion burden as a function of proximal-to-distal anatomic nerve positions.

Results

Demographic and clinical data including genetic defects for all patients confirmed with early or late-onset NF2 and NF2-PNP are given in Table 1. All patients had bilateral vestibular nerve schwannomas (VNS). Genetic analysis using peripheral leucocytes was successful in all patients except patient 6, which might be due to mosaicism in this patient. Detailed clinical and electrophysiological parameters were obtained (Table 2) to classify NF2-PNP severity and localization pattern.
Table 1

Patient history and demographic and clinical data including genetic characterization

Patient

1

2

3

4

5

6

7

8

Age

49

39

22

23

58

57

11

32

Sex

Male

Male

Male

Male

Male

Female

Female

Female

Age of NF2 onset

20

5

10

12

39

40

8

17

Early/late-onset phenotype

Early

Early

Early

Early

Late

Late

Early

Early

NF2-PNP severity

Severe

Severe

Moderate

Moderate

Moderate

Subclinical

Severe

Severe

Family history

Neg.

Neg.

Pos.

Neg.

Neg.

Neg.

Neg.

Neg.

Mutation

c.448-1G > A splicing

c.352-354del3 bp small in-frame deletion

c.448-1G > A splicing

c.169C > T nonsense mutation

Exon 15 deletion

Not found

c.1021C > T; stop mutation

Deletion of 5′ region of exon 1

Cranial tumors beside VNS

3

4

5

4

2

1

2

4

Spinal tumors, intra-axial

1

0

4

3

0

0

2

1

Spinal tumors, extra-axial

4

7

6

6

0

0

0

5

Prior surgical interventions beside VNS

2

2

1

3

1

2

1

4

Table 2

Clinical and electrophysiological data for lower extremities

Patient: 

1

2

4

5

6

Leg:

Left

Right

Left

Right

Left

Right

Left

Right

Left

Right

Sensibility

None

None

Decreased

Normal

Normal

Normal

Ankle jerk reflex

No reflexes

Decreased

Decreased

Decreased

Normal

Paresis

None

Yes

Yes

Feet dorsiflexion

None

None

Muscular atrophy

Yes

Yes

None

None

None

PNP

Severe

Severe

Moderate

Subclinical

Subclinical

Motor nerve conduction

 DML (ms)

Tibial (<5.1)

n.d.

n.d.

5.5

4.9

5.8

6.2

3.5

4.1

2.4

2.9

Peroneal (<4.8)

5.6

n.d.

4.8

4.6

6.3

n.d.

6.6

n.d.

3.2

4.0

 Distal CMAP (mV)

Tibial (>5.0)

0

0

0.2

8.3

15

16

1.4

0.9

4.0

4.6

Peroneal (>4.0)

0.3

0

0.3

1.1

0.8

0

0.6

0

2.1

0.6

 Proximal CMAP (mV)

Tibial (>5.0)

0

0

0

5,8

12

13

0.8

0.8

3.6

2.4

Peroneal (>4.0)

0,2

0

0.3

0.8

0.8

0

0.5

0

1.7

0.6

 Conduction velocity (m/s)

Tibial (>40.6)

0

0

0

39

40

45

36

39

42

51

Peroneal (>41.7)

41

0

36

38

35

0

36

0

47

40

 Minimal F-wave latency (ms)

Tibial (58)

n.d.

n.d.

n.d.

66

55

55

n.d.

n.d.

49

49

Peroneal (57)

n.d.

n.d.

n.d.

n.d.

61

n.d.

n.d.

n.d.

n.a.

49

Sensory nerve conduction

 Amplitude (mV)

Sural (>3.8)

1.1

0

3.5

18

9.5

14

2.9

7.1

3.4

5

 Conduction velocity (m/s)

Sural (>39.3)

39

0

35

49

40

50

47

47

51

52

Detailed electrophysiological examination of patient 3 was not achievable; his clinical symptoms included muscle cramps of all extremities, dysesthesia in distally in the legs, and mild hyporeflexia of lower extremities. All patients exhibit axonal neuropathy. Reductions in nerve conduction velocities may be due to predominant loss of larger fibers or to some degree of additional demyelination

CMAP compound muscle action potential, DML distal motor latency, n.d. no motor or sensory potential detectable, n.a. not available

Lower extremities: analysis of fascicular T2 lesion burden

A wide spectrum of non-compressive, intermediate and compressive fascicular T2 nerve lesions was observed and categorized as shown in Fig. 1. Microlesions (type I) were highly frequent in all patients, and intermediate lesions (type II) were also found in all patients on both sides, whereas compressive macrolesions (type III) were distributed much more sparsely. Table 3 displays the individual quantitative information of cumulative lesion burden within all evaluated categories. Both clinical and electrophysiological signs of PNP were observed even in the absence of any compressive macrolesion (type III), as in patient 1 (severe PNP) and patient 4 (moderate PNP) on the right side, and in patient 5 (moderate PNP) and patient 6 (subclinical PNP) on the left side.
Fig. 1

Spectrum of non-compressive and compressive fascicular T2 lesions in NF2 on axial sections of the sciatic nerve. All panels show axial sections with magnifications of the sciatic nerve at mid-thigh level. In the upper row, representative lesion types are shown classified according to the following criteria: (I) non-compressive fascicular microlesions (<2 mm diameter), (II) intermediate fascicular lesions (≥ 2 mm and <5 mm diameter), and (III) compressive macrolesions (≥5 mm diameter). In the lower row, the four different categories classifying the extent of fascicular involvement in lesion type I are shown: (0) all fascicles normal (1) T2 lesions of individual fascicles (less than 25 % of all fascicles involved on a given 2D axial imaging slice), (2) T2 lesions of individual fascicles involving 25 % or more, but less than 75 % of fascicles) and (3) T2 lesions of all or almost all fascicles (>75 %)

Table 3

Individual lesion counts for all categories

Patient

Average grading

type I lesions

Total count

type II lesions

Total count

type III lesions

Left

Right

Left

Right

Left

Right

1 (early onset, severe PNP)

1.74

1.20

36

30

2

0

2 (early onset, severe PNP)

1.85

 1.34

19

24

12

9

3 (early onset, moderate PNP)

1.08

0.99

13

17

5

1

4 (early onset, moderate PNP)

0.70

0.97

2

5

1

0

5 (late onset, mild PNP)

1.20

1.15

19

12

0

6

6 (late onset, subclinical PNP)

0.14

 0.24

2

2

0

1

The overall lesion burden was distributed diffusely: across all patients, no single nerve segment exhibited noticeably more lesions than any other, but compressive macrolesions were very seldom found below the knee.

Early onset phenotype

Cumulative lesion burdens in NF2-PNP of early onset NF2 for the frequent microlesions and intermediate lesions are plotted in Fig. 2. The difference between patients with severe and moderate NF2-PNP was most marked for non-compressive fascicular T2 lesions and intermediate lesions. In patients with early onset NF2 and severe NF2-PNP (patients 1 and 2), the severity of cumulative fascicular T2 lesion burden was considerably higher than in patients with early onset NF2 and moderate NF2-PNP (patients 3 and 4). Representative imaging findings are shown in Fig. 3.
Fig. 2

Fascicular T2 lesion burden of early onset and late-onset NF2. Cumulative lesion counts of two of the three categories (a, c microlesion grading; b, d intermediate lesions) are separately plotted against anatomical slice positions. From proximal to distal, “prox.” denotes slice positions starting at the lower lumbosacral plexus (L3 roots downward) to proximal thigh, “mid.” refers to slice positions from mid-thigh to knee region and “dist.” refers to slice positions from the knee to ankle regions. The low number of compressive macrolesions is displayed in Table 3. Cumulative lesion burden is higher for severe versus moderate early onset NF2-PNP in all three lesion categories, though most marked in type I (non-compressive microlesions) and type II (intermediate) lesions. Likewise, cumulative lesion burden is higher for moderate versus subclinical late-onset NF2-PNP in all three lesion categories, though most marked in type I (non-compressive microlesions) and type II (intermediate) lesions

Fig. 3

Representative microstructural images of cumulative fascicular T2 lesion burden in early onset NF2 moderate NF2-PNP (a, b) is shown versus severe NF2-PNP (c, d) of early-onset NF2-PNP. Images correspond to axial sections at mid-thigh with magnifications of the sciatic nerve in a, and c, and mid lower leg levels with magnifications of the tibial nerve in b and d. Note severe atrophy of thigh muscles in c. Arrowhead nerve fascicle with normal signal intensity and caliber; small arrow microlesion with altered T2 signal but no or only slight enlargement; large arrow intermediate lesion measuring more than 2 mm

Late-onset phenotype

Cumulative lesion burdens in NF2-PNP of late-onset NF2 for the frequent microlesions and intermediate lesions are plotted in Fig. 2. The difference was most marked for microlesions and intermediate lesions. In late-onset NF2 and moderate NF2-PNP (patient 5) the severity of cumulative lesion burden was considerably higher than in late-onset NF2 and subclinical NF2-PNP (patient 6). Representative imaging findings are shown in Fig. 4.
Fig. 4

Representative microstructural images of cumulative fascicular T2 lesion burden in late-onset NF2 Subclinical NF2-PNP (a, b) is shown versus moderate NF2-PNP (c, d) of late-onset NF2. Images correspond to axial sections at mid-thigh with magnifications of the sciatic nerve in a and c, and mid lower leg levels with magnifications of the tibial nerve in b and d. Only one microlesion is observed in the peroneal part of the sciatic nerve in panel a and no lesions in panel b while almost all fascicles are involved in c and d. Arrowhead nerve fascicle with normal signal intensity and caliber; small arrow microlesion with altered T2 signal but no or only slight enlargement; large arrow intermediate lesion measuring more than 2 mm

Upper extremities

Large-coverage fascicular T2 sampling MRI was also performed in those patients with symptomatic NF2-PNP involving the upper extremities (patients 1, 7, and 8). Due to RF-field inhomogeneity around the neck and shoulder region and occasional motion artifacts in the upper arms, a comprehensive quantitative analysis of the upper extremities was not intended. However, the qualitative results obtained are similar to the results seen in the lower extremities. Imaging pathomorphology revealed fascicular T2 lesion burden composed of cumulating non-compressive fascicular T2 microlesions as well as few intermediate lesions, while no compressive macrolesions lesions were detected.

Discussion

As the principal result of this investigation, diffusely distributed fascicular T2 lesions are found as the predominant pathomorphological correlate of NF2-PNP. The cumulative proximal-to-distal burden of these non-compressive fascicular microlesions and intermediate lesions, in contrast to compressive mass lesions, was found to be closely associated with symptom severity of clinically manifest NF2-PNP. The total of eight patients with NF2-PNP represents the second largest group with this rare hereditary disorder reported in the literature. In six of the eight individual cases presented here, NF2-PNP was present even in the absence of any compressive mass lesions along the PNS in at least one extremity, including spinal nerves, plexus, and peripheral nerves. The existence of “multiple tumorlets originating along the length of the peripheral nerves” as the cause for this polyneuropathy syndrome has actually been put forward as one hypothesis previously [14], which could now be tested in vivo for the first time. In previous enquiries as well as in our study, NCS of NF2-PNP with decreased SNAP and CMAP imply axonal loss as the principal feature of NF2-PNP [14]. Several patients in the literature as well as in our study additionally show reductions in nerve conduction velocity, which may be due to predominant loss of larger fibers or to an additional demyelinating component [13, 14, 15]. Complementing these studies, few histopathologic publications can be found in the literature. Apart from gross tumor growth, several groups reported small endoneurial tumorlets, diffuse proliferation of Schwann cells, demyelination, and also proliferation of perineurial cells in a total of 12 sural nerve biopsies [12, 13, 14, 15, 28]. These versatile histopathological findings of endoneurial tumorlets, diffuse proliferation of Schwann cells and demyelination obtained from sural nerve biopsies might at least in part represent the substrates of imaging pathomorphology described in this study. While we did not obtain nerve biopsies from the patients in this study, these structural changes may all be conceived of as histological alterations leading to an increase in T2 relaxation time and thereby to the observed fascicular T2 lesions [29, 30].

Interestingly, the correlation between fascicular pathomorphology and severity of clinical manifestation was most clearly established when separating the two phenotype categories of NF2 into early onset NF2 with moderate or severe PNP, and late-onset NF2 with subclinical or moderate PNP [27, 31]. This significant correlation after separating the two phenotypes suggests that the histopathological alterations underlying fascicular T2 lesions of NF2 may be different between phenotypes. The existing pathohistological literature on NF2 peripheral nerve lesions cannot support nor contradict this hypothesis since, to our knowledge, none of the reported biopsies have been from patients with the late-onset phenotype.

For clinicians treating patients affected with NF2-PNP, it is often very difficult but highly relevant to differentiate between a mostly diffuse PNP or a solitary compressive mass lesion of the PNS, which may be surgically removed. The pathomorphological imaging correlates of NF2-PNP may contribute to conceive of NF2-PNP as a predominantly diffuse polyneuropathy. Our results underline the importance to consider the possibility that even in the presence of solitary mass lesions, the manifestation and severity of clinical symptoms may be attributed not or at least not only to those lesions amenable to surgical intervention. A focused imaging characterization by fascicular T2 sampling including the non-compressive lesion burden might in the future assist the decision whether symptoms of NF2-PNP are to a significant degree related to compressive lesions so that peripheral nerve surgery in the affected NF2 patient may be indicated. Alternatively, the absence of compressive lesions and/or the presence of a high non-compressive lesion burden diminish the chance that patients with NF2-PNP will benefit from peripheral nerve surgery.

This study comes with some methodological limitations. A large number and variety of nerve alterations in terms of nerve signal and morphology had to be categorized for quantitative analysis. The distinction of lesions larger than 5 mm as compressive lesions is admittedly somewhat arbitrary, and the compressive effect of those lesions may in truth not only depend on size. Also, it remains unknown which degree of fascicular enlargement or tumor formation ultimately represents axonal loss or demyelinating damage in the respective fascicle and its neighboring fascicles. Since electrophysiological parameters provide excellent functional data on nerve function but technically limited information on spatial distribution, an exact nerve-segment-wise correspondence between imaging and electrophysiology was not intended. Instead, the methods complement each other especially when multiple lesions are present.

On a broader level, the novel method of high-resolution large-coverage T2 sampling may be applied in numerous other investigations of the spatial dissemination and fascicular pathomorphology of the polyneuropathies. Future studies of other systemic hereditary and non-hereditary polyneuropathies can assess whether diffuse proximal-to-distal lesion burden or few solitary lesions contribute to the clinical manifestation of disease and the progression of symptom severity. Furthermore, the spatial pattern of nerve lesions may result in insights that enhance our understanding of the pathophysiology of the respective disease as in diabetic neuropathy. In others, as in NF2, it may lead to better diagnostic possibilities directly influencing clinical care of affected patients.

Notes

Acknowledgments

This work was supported by a postdoctoral-fellowship granted to P.B. and to M.P. from the Medical Faculty of the University of Heidelberg and a grant to M.P. and M.B. from the German Osteoarthritis Foundation (Deutsche-Arthrose-Hilfe e.V.) [P215-A482].

Conflicts of interest

The authors report no conflicts of interests.

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • P. Bäumer
    • 1
  • V. F. Mautner
    • 3
  • T. Bäumer
    • 3
  • M. U. Schuhmann
    • 4
  • M. Tatagiba
    • 5
  • S. Heiland
    • 2
  • T. Kaestel
    • 2
  • M. Bendszus
    • 1
  • M. Pham
    • 1
  1. 1.Department of NeuroradiologyHeidelberg University HospitalHeidelbergGermany
  2. 2.Division of Experimental Radiology, Department of NeuroradiologyHeidelberg University HospitalHeidelbergGermany
  3. 3.Department of NeurologyUniversity Hospital EppendorfHamburgGermany
  4. 4.Section of Pediatric Neurosurgery, Department of NeurosurgeryTübingen University HospitalTübingenGermany
  5. 5.Department of NeurosurgeryTübingen University HospitalTübingenGermany

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