High-resolution ultrasonography of peripheral nerves in neurofibromatosis

Neurofibromatosis is a group of genetic diseases which manifests mainly in
neurological and cutaneous symptoms. There are three subtypes; type 1 (NF1, Von
Recklinghausens disease), type 2 (NF2), and schwannomatosis.

NF1 has the highest incidence (1 in 3 000) and manifests itself by multiple
cafe-au-lait spots. Patients have a higher chance to develop peripheral
neurofibromas, gliomas of the optical tract and sarcomas. Skeletal deformaties
are also seen in NF1. Due to the cafe-au-lait spots and the skeletal
deformaties, NF1 is usually diagnosed at a young age [Korf, 2015].

NF2 (incidence 1 in 25 000) manifests itself by bilateral pontine angle tumors,
spinal tumors and multiple meningeomas. Patients are often diagnosed in their
second decade of life [Evans, 2015].

Schwannomatosis is a rare disease, with an annual incidence of 0.58 per 1 000
000. Patients usually present with multiple symptomatic schwannomas. Patients
are often diagnosed around their 4th decade in life [Yohay et al. 2015].

Neurofibromas in NF1 can be located in the skin, but also in peripheral nerves
or near a nerve root. They can be plexiform or nodular. These non-cutaneous
neurofibromas can develop in malignant peripheral nerve sheat tumors (MPNST)
[Korf, 2015].
Peripheral neuropathies are rarely seen in NF2, since there are mainly
abnormalities of the central nervous system [Evans, 2015].
Schwannomas can develop in cranial nerves, nerve roots and in peripheral nerves
[Yohay et al. 2015].

Imaging of these abnormalities is in full development. In hte past
neurofibromas, schwannomas and MPNSTs were mainly depicted by MRI, since it is
highly sensitive in soft-tissue abnormalities. However, MRI is expensive,
patients can be claustrofobic and it is impracticle when multiple nerves need
to be depicted. Due to the recent development of high-resolution
ultrasonography (HRUS) it is possible to depict morphologic abnormalities of
peripheral nerves in a cost-effective and patient-friendly way [Goedee 2013].

In recent years, there have been a number of case-reports on HRUS in patients
with NF. Irregular, hypoechoic enlargements were seen with hemorrhagic,
calcified or necrotic mateerial [Kara 2010, Karabacak 2014, Zarchi 2014, Sehgal
2009]. The incidence and the clinical consequences of abnormalities in
peripheral nerves in patients with neurofibromatosis is not known. Possibly,
HRUS is able to depict neurofibromas and schwannomas at a non-symptomatic
stage. It is possible that this has consequences for treatment and outcome in
this patient group.

The aim of this study is to further explore ultrasonographic abnormalities of
peripheral nerves in patients with NF and their relation with symptoms,
findings in neurological examination and electrophysiological characteristics.
Primary objective: What are the ultrasonographic characteristics of peripheral
nerves in patients with NF?
Secondary objective: What is their relation with symptoms, findings in
neurological examination and electrophysiological characteristics?


Based on the findings in the pilot study ultrasonography will be performed as
well after 1 year of follow-up (if patients signs for informed consent again).
Primary goal of follow-up is to further explore the development of sonographic
abnormalities over time in neurofibromatosis
Secondary goal is to determine the relation between development of sonographic
abnormalities and clinical symptoms over time

This study is a pilot study, in which peripheral nerves of patients with NF
will be examined both by ultrasound and by electrodiagnostic tests.

Patients will undergo an anamnesis and physical examination, in which questions
and tests will be focused on symptoms that can be found often in
neurofibromatosis. Patients will undergo a HRUS of the peripheral nerves, in
which median, ulnar, fibular, tibial, sural nerve and brachial plexus will be
investigated bilateral. In addition patients will undergo electrodiagnostic
testing, in which median, ulnar, fibular, tibial and sural nerve will be
investigated unilateral (in order to limit burden for participating patients).

Based on the findings at the primary sonography visit a sonography will be
performed as well after 1 year of follow-up. Patients will receive a new
patient information letter and will sign informed consent again. At follow-up
patients will undergo sonography, anamnesis and physical examination by the
same protocol as at inclusion. Electrodiagnostic testing will nog be performed
during follow-up in order to limit burden for patients.

The risks associated to participating are negligible. There are no known
harmful effects of ultrasonography or electrodiagnostic testing.
There is a small burden for patients, because they need to invest time. Since
the knowledge of neurofibrosis will be enlarged, we believe this investment is
justifiable.

Burden for the follow-up visit is identical to that of the primary visit, with
the exception of electrodiagnostic testing,which will not be performed during
follow-up in order to limit burden for patients. New informed consent will be
obtained for the follow-up visit.