prevalence and significance of cranial nerve imaging
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Prevalence and Significance of CranialNerve Imaging Abnormalities in
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Citation Bartholomew, Ryan Alexander. 2019. Prevalence and Significanceof Cranial Nerve Imaging Abnormalities in Patients With HereditaryNeuropathies. Doctoral dissertation, Harvard Medical School.
Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:41971539
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Scholarly Report submitted in partial fulfillment of the MD Degree at Harvard Medical 1
School 2
Date: 26 February 2019 3
Student Name: Ryan Alexander Bartholomew 4
Scholarly Report Title: Prevalence And Significance Of Cranial Nerve Imaging Abnormalities 5
In Patients With Hereditary Neuropathies 6
Mentor Name(s) and Affiliations: C. Eduardo Corrales, MD, Division of Otolaryngology—7
Head and Neck Surgery, Brigham and Women’s Hospital, Department of Otolaryngology, 8
Harvard Medical School. 9
Collaborators, with Affiliations: 10
Amir A. Zamani, MD, Division of Neuroradiology, Brigham and Women’s Hospital 11
Grace S. Kim, MD, Department of Otolaryngology-Head and Neck Surgery, Stanford University 12
School of Medicine 13
Jennifer C. Alyono, MD, Department of Otolaryngology-Head and Neck Surgery, Stanford 14
University School of Medicine 15
Haley Steinert, BA, Department of Neurology, University of Colorado School of Medicine 16
Vera Fridman, MD, Department of Neurology, University of Colorado School of Medicine 17
Reza Sadjadi, MD, Department of Neurology, Massachusetts General Hospital 18
Robert K. Jackler, MD, Department of Otolaryngology-Head and Neck Surgery, Stanford 19
University School of Medicine 20
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Title: Prevalence And Significance Of Cranial Nerve Imaging Abnormalities In Patients 31
With Hereditary Neuropathies 32
Purpose: To estimate the prevalence and significance of cranial nerve (CN) imaging findings in 33
patients with hereditary neuropathy. 34
Methods: We retrospectively analyzed data from patients at four tertiary academic medical 35
centers with hereditary neuropathy diagnoses who had undergone gadolinium enhanced magnetic 36
resonance imaging (MRI) of the brain between 2004 and 2018. MRI scans, as well as computed 37
tomography (CT) imaging when available, were reviewed and bivariable analysis was performed 38
to identify predictors of CN abnormalities on imaging. 39
Results: Among 39 patients, 11 had CN deficits (28.2%). Out of the 8 patients who had CN 40
abnormalities on imaging (20.5%), 4 had CN deficits with only 2 of these patients having 41
imaging abnormalities in the CNs with deficits. Imaging abnormalities were found in varied CNs 42
and included nerve thickening and enhancement on MRI and nerve foramina enlargement on CT. 43
MRIs obtained for evaluation of CN deficit evaluation had a statistically significant increased 44
likelihood of imaging abnormalities. However, CN deficits themselves were not predictive of 45
imaging abnormalities. 46
Conclusions: Thickening and enhancement of CNs on MRI may be found in 1/5 of patients with 47
hereditary neuropathies and are inconsistently associated with clinical deficits. These imaging 48
findings, which can mimic certain neoplastic processes, are unlikely to require surgical 49
management in these patients and instead may be manifestations of the underlying genetic 50
neuropathy. 51
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Table of Contents 62
Title Page P. 1 63
Abstract P. 2 64
Glossary of Abbreviations P. 4 65
Scholarly Project Question P. 5 66
Author Contributions P. 6 67
Appendix: Manuscript P. 7-19 68
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Glossary of Abbreviations 93
CN: cranial nerve 94
MRI: magnetic resonance imaging 95
CT: computed tomography 96
CMT: Charcot-Marie-Tooth 97
HMSN: hereditary motor and sensory neuropathy 98
IAC: internal auditory canal 99
EMG: electromyography 100
HNPP: hereditary neuropathy with liability to pressure palsy 101
ESRD: end stage renal disease 102
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Scholarly Project Question 124
Hereditary neuropathies, i.e. Charcot-Marie-Tooth Disease (CMT), are a heterogeneous group of 125
rare genetic conditions characterized by peripheral motor and sensory deficits. The burden of 126
disease is typically due to involvement of the peripheral nerves of the arms and legs. Despite the 127
inclusion of cranial nerves I and III-XII as part of the peripheral nervous system, descriptions of 128
cranial nerve involvement are less common. What is the prevalence and significance of cranial 129
nerve abnormalities on imaging in patients with hereditary neuropathies? 130
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Author Contributions 155
Ryan Bartholomew: Ryan took the lead in the design and organization of this multicenter study. 156
He tabulated and analyzed the data, contributed to imaging interpretation, and wrote the 157
manuscript which will be submitted to Neurology for publication consideration. He prepared the 158
IRB application at Massachusetts General Hospital and Brigham and Women’s Hospital, which 159
was used as a template for similar applications at Stanford and University of Colorado Denver. 160
He identified the cohort of patients within the Brigham and Women’s Hospital and 161
Massachusetts Hospital system meeting study inclusion criteria using the Partners Research 162
Patient Data Registry (RPDR). He coordinated with collaborators at the University of Colorado 163
and at Stanford to identify similar patient cohorts at those institutions. Ryan collected the 164
relevant demographic, imaging, and clinical presentation data from the BWH and MGH cohort 165
and then added similar data collected by collaborators at Colorado and Stanford to the overall 166
dataset. In addition to personally providing a preliminary read of the imaging data, he elicited 167
reads of the images from trained physicians locally and at the collaborating institutions. He 168
conducted all statistical analyses. He wrote the manuscript and prepared the figures and tables—169
incorporating the expert feedback of his mentors and collaborators in the final product. He is 170
preparing to submit the manuscript to Neurology for consideration as a smaller scope study (all 171
studies with less than 50 subjects). 172
Amir A. Zamani, MD: imaging interpretation, manuscript editing 173
Grace S. Kim, MD: data collection, imaging interpretation, manuscript editing 174
Jennifer C. Alyono, MD: imaging interpretation, manuscript editing 175
Haley Steinert, BA: data collection, manuscript editing 176
Vera Fridman, MD: manuscript editing 177
Reza Sadjadi, MD: manuscript editing 178
Robert K. Jackler, MD: manuscript editing 179
C. Eduardo Corrales, MD: study design, imaging interpretation, manuscript editing 180
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Prevalence and significance of cranial nerve imaging abnormalities in 185
patients with hereditary neuropathies 186
Ryan A. Bartholomew, BS1; Amir A. Zamani, MD2; Grace S. Kim, MD3; Jennifer C. Alyono, MD3; 187 Haley Steinert, BA4, Vera Fridman, MD4; Reza Sadjadi, MD5; Robert K. Jackler, MD3, C. Eduardo 188 Corrales, MD1 189
1Harvard Medical School 190 Brigham and Women’s Hospital 191 Division of Otolaryngology-Head and Neck Surgery 192 45 Francis Street 193 Boston, MA 02115 194 195 2Harvard Medical School 196 Brigham and Women’s Hospital 197 Division of Neuroradiology 198 45 Francis Street 199 Boston, MA 02115 200 201 3Stanford University School of Medicine 202 Department of Otolaryngology-Head and Neck Surgery 203 Division of Otology & Neurotology 204 801 Welch Road, 2nd Floor 205 Stanford, CA 94305 206 207 4University of Colorado School of Medicine 208 Department of Neurology 209 12631 East 17th Avenue 210 Aurora, CO 80045 211 212 5Harvard Medical School 213 Massachusetts General Hospital 214 Department of Neurology 215 55 Fruit Street 216 Boston, MA 02114 217 218 Corresponding Author: 219 C. Eduardo Corrales, MD 220 Division of Otolaryngology—Head and Neck Surgery 221 Brigham and Women’s Hospital, Boston, MA. 222 Department of Otolaryngology, Harvard Medical School. 223 45 Francis Street, Boston MA 02115 224 [email protected] 225 226 Key Words: cranial nerves, Charcot Marie Tooth, hereditary neuropathy, hereditary motor and sensory 227 neuropathy, skull base, MRI 228 Running Header: Cranial nerve imaging abnormalities in hereditary neuropathies 229 The authors have no relevant financial disclosures. 230 Funding Sources: none. 231 232
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Abstract 233
Objective To estimate the prevalence and significance of cranial nerve (CN) imaging findings in 234
patients with hereditary neuropathy. 235
Methods We retrospectively analyzed data from patients at four tertiary academic medical 236
centers with hereditary neuropathy diagnoses who had undergone gadolinium enhanced magnetic 237
resonance imaging (MRI) of the brain between 2004 and 2018. MRI scans, as well as computed 238
tomography (CT) imaging when available, were reviewed and bivariable analysis was performed 239
to identify predictors of CN abnormalities on imaging. 240
Results Among 39 patients, 11 had CN deficits (28.2%). Out of the 8 patients who had CN 241
abnormalities on imaging (20.5%), 4 had CN deficits with only 2 of these patients having 242
imaging abnormalities in the CNs with deficits. Imaging abnormalities were found in varied CNs 243
and included nerve thickening and enhancement on MRI and nerve foramina enlargement on CT. 244
MRIs obtained for evaluation of CN deficit evaluation had a statistically significant increased 245
likelihood of imaging abnormalities. However, CN deficits themselves were not predictive of 246
imaging abnormalities. 247
Conclusions Thickening and enhancement of CNs on MRI may be found in 1/5 of patients with 248
hereditary neuropathies and are inconsistently associated with clinical deficits. These imaging 249
findings, which can mimic certain neoplastic processes, are unlikely to require surgical 250
management in these patients and instead may be manifestations of the underlying genetic 251
neuropathy. 252
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Introduction 256
Hereditary neuropathy, also referred to as Charcot-Marie-Tooth disease, encompasses a 257
heterogeneous group of rare genetic conditions characterized by motor and sensory deficits, the 258
most common of which is hereditary motor and sensory neuropathy (HMSN). Implicated 259
mutations disrupt the formation and maintenance of axonal myelination and integrity. 260
Impairment of these processes preferentially impact the larger and longer neuronal fibers of the 261
extremities, with cranial nerve (CN) involvement being less frequently reported. Cranial nerve 262
pathology on imaging is limited to case reports. Described abnormalities on magnetic resonance 263
imaging (MRI) include smooth hypertrophy, mild enhancement with gadolinium, or both of 264
varied CNs.1-6 Computed tomography (CT) has identified enlargement of skull base foramina.1,2,7 265
Imaging abnormalities have been identified in patients with,2,7 and without,1,3-5 attributable 266
symptoms. Even among the reported patients with CN deficits, many of the abnormally 267
appearing CNs were asymptomatic. Moreover, CN deficits also occur in the absence of imaging 268
abnormalities.6,8-10 269
The aim of our multicenter study was to further characterize the prevalence and 270
significance of CN imaging abnormalities in patients with hereditary neuropathies. We analyzed 271
the appearance of CNs on gadolinium enhanced MRI brain scans from patients with hereditary 272
neuropathy. When available, CT imaging was also reviewed. Patient demographics and clinical 273
data, including CN deficits, were investigated to ascertain associations with imaging 274
abnormalities. 275
Methods 276
Patients 277
The Brigham and Women’s Hospital, Massachusetts General Hospital, Stanford Medical 278
Center, and University of Colorado School of Medicine institutional review boards approved the 279
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study. Through electronic medical record databases at these tertiary care referral centers, patients 280
with a hereditary neuropathy diagnosis who had undergone a gadolinium enhanced MRI of the 281
brain or skull base between 2004-2018 were retrospectively identified. Inclusion criteria for 282
MRI scans was presence of T1-weighted sequences with and without gadolinium, visualization 283
of the skull base, and minimal motion artifact. Collected patient data included gender, hereditary 284
neuropathy diagnosis, age at time of MRI imaging, imaging indication, and signs and symptoms 285
suggestive of CN deficits. 286
Imaging 287
MRI sequences were reviewed using axial, coronal, and sagittal planes. CN 288
abnormalities, including enhancement and thickening, were noted. When available, CT scans of 289
the head were also reviewed for enlargement of CN foramina. Review of imaging was conducted 290
by physicians trained in either neuroradiology or skull base surgery. Each scan was analyzed 291
independently by two reviewers who were blinded to patient name, demographics, and clinical 292
history. Marginal findings were called abnormal only when they were corroborated by findings 293
on successive slices and alternative planes or by corresponding CN foramina enlargement on CT 294
(when available). 295
Statistical Analysis 296
Descriptive analysis was performed to characterize patient demographics, clinical data, 297
and imaging findings. Bivariable comparisons were performed using Student’s T-test for means 298
and Fisher’s exact tests for categorical variables. Alpha threshold for significance was tested at a 299
level of 0.05. All statistical analyses were performed using JMP Pro v14 (SAS Institute, Cary, 300
NC). 301
Results 302
Patients 303
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A total of 41 patients were identified (Supplementary Figure 1). Two patients were 304
excluded due to inadequate imaging quality, leaving 39 patients (Table 1). The mean patient age 305
was 48.9 ± 24.1 years (range: 3 – 90 years) with an equal proportion of males (51.3%) and 306
females (48.7%). HMSN diagnoses were distributed among five categories: HMSN (unspecified 307
type) (46.2%), hereditary neuropathy with liability to pressure palsies (HNPP, 10.3%), HMSN1 308
(30.8%), HMSN2 (10.3%), and HMSN5 (2.6%). CN deficits were documented in 28.2% of 309
patients. Examples included facial and tongue paresis and/or paresthesia, sensorineural hearing 310
loss, tinnitus, and diplopia (Supplementary Table 1). 311
Imaging Characteristics 312
Most patients had MRIs protocolled for evaluation of the brain (92.3%), with a minority 313
having dedicated skull base MRIs (7.7%) (Table 1). A minority of patients received an MRI for 314
the indication of CN deficit evaluation (15.4%). The prevalence of CN abnormalities on MRI 315
was 20.5% (Supplementary Table 1). Patients with abnormalities had CN thickening only (3/8), 316
CN enhancement only (1/8), or both thickening and enhancement in the same or different CNs 317
(4/8) (Figures 1 and 2). There was an equal distribution of patients with the same CNs abnormal 318
bilaterally (symmetric, 4/8) and different CNs abnormal on the left vs. the right (asymmetric, 319
4/8). Patients had imaging abnormalities in the following CNs, either unilaterally or bilaterally: 320
CN III (1/8), CN V (5/8), CN VII distal to the internal auditory canal (5/8), and the CN VII/VIII 321
complex in the IAC (4/8). Half of patients with imaging abnormalities had CN deficits (4/8), 322
with only half of that subset having deficits that corresponded to at least some of the abnormally 323
appearing CNs (2/8). 324
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Fifteen patients had CT imaging of the head (38.5%). Findings of CN foramina 325
enlargement on CT which corresponded to CN thickening on MRI were identified 326
(Supplementary Table 1). 327
Predictors for Cranial Nerve Abnormalities on MRI 328
Bivariable analyses were performed to identify factors associated with CN abnormalities 329
on MRI (Table 1). CN abnormalities on MRI were not associated with patient age (abnormal 330
MRI mean = 43.5 ± 19.6 years vs. normal MRI mean = 50.3 ± 25.2 years, P = 0.42), sex 331
(females 21.1% vs males 20.0%, P = 1.0), MRI protocol (brain 16.7 % vs dedicated skull base 332
66.7 %, P = 0.10), or the availability of CT imaging (available 26.7% vs. not available 16.7%, P 333
= 0.69). MRIs performed for the indication of CN deficit evaluation were more likely to be 334
abnormal (CN deficit indication 66.7% vs other indication 12.1%, P = 0.01), although CN 335
deficits themselves were not predictive of imaging abnormalities (CN deficits 36.4% vs no CN 336
deficits 14.3%, P = 0.19). Sample size limitations precluded subgroup analyses of hereditary 337
neuropathy type. 338
Discussion 339
Ours is the first study describing a cohort of patients with hereditary neuropathy who 340
have undergone brain MRIs. Whereas CN involvement on MRI has rarely been described in 341
hereditary neuropathy, we found a 20.5% prevalence of CN pathology. Similar to prior case 342
reports,1-6 thickening and/or enhancement of varied CNs were identified. For patients with CN 343
thickening on MRI, corresponding CN foramina enlargement was present on available CT 344
imaging. CN pathology on imaging was inconsistently associated with clinical deficits—only 345
two of the eight patients with imaging abnormalities had clinical deficits which could be 346
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attributed to the abnormally appearing CNs. Moreover, while MRIs performed for the indication 347
of CN deficit evaluation were positive predictors of imaging abnormalities, CN deficits were not. 348
Many challenges are inherent to evaluating CN imaging abnormalities in this patient 349
population. The rarity of theses conditions makes assembly of a large cohort difficult, which is 350
further compounded by the availability of brain MRIs. CN assessment was also limited by a 351
paucity of dedicated thin slice imaging of the skull base, which may have limited our ability to 352
identify subtle abnormalities. Moreover, care must be taken when applying conclusions drawn 353
from our cohort of heterogenous hereditary neuropathies to any specific condition. One 354
particular hypothesis for future studies is whether imaging abnormalities may occur more 355
frequently in HMSN1, which is predominantly characterized by demyelination and can have 356
features of nerve hypertrophy on peripheral nerve biopsy, than in HMSN2, which is 357
predominantly characterized by axonal degeneration and rarely hypertrophy. Our study was 358
unable to answer this question, with five of the patients with imaging abnormalities having an 359
unspecified type of HMSN and the remaining three having either HMSN1 or HNPP 360
(Supplementary Table 1). 361
Thickening and enhancement of CNs on MRI may be found in 1/5 of patients with 362
hereditary neuropathies and are inconsistently associated with clinical deficits. These imaging 363
findings, which can mimic certain neoplastic processes, are unlikely to require surgical 364
management and instead may be manifestations of the underlying genetic neuropathy. 365
366
367
368
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Table 1. Patient demographics, disease characteristics, and imaging characteristics 369
Variable Quantity or Mean
(Frequency %), N=39
Bivariable comparison of CN
abnormalities on MRI by given
variable: P-Value
Age (years)
Abnormalities on imaging
No abnormalities on imaging
48.9
43.5
50.3
0.42
Sex:
Male
Female
20 (51.3)
19 (48.7)
1.00
HMSN Diagnosis:
HMSN (unspecified type)
HNPP
HMSN1
HMSN2
HMSN5
18 (46.2)
4 (10.3)
12 (30.8
4 (10.3)
1 (2.6)
N/A
Neuropathy pathology
Unspecified
Demyelinating
Axonal
Intermediate
18 (46.2)
16 (41.0)
5 (12.8)
0
N/A
MRI protocol Brain MRI
Dedicated skull base MRI
36 (92.3)
3 (7.7)
0.10
CN abnormalities on MRI Type of abnormalities
Nerve thickening only
Nerve enhancement only
Both
Symmetry of abnormalities
Symmetric abnormalities
Asymmetric abnormalities
CNs Involved (unilateral or bilateral)
CN III
CN V
CN VII (distal to the IAC) CN VII/VIII complex in the IAC
8 (20.5)
3
1
4
4
4
1
5
5 4
N/A
CN deficits
Concurrent CN abnormalities on MRI
Any CN(s)
Corresponding CN(s)
11 (28.2)
4
2
0.19
Indication for MRI imaging
CN deficit
Other
6 (15.4)
33 (84.6)
0.01
CT available
Nerve foramina enlargement
15 (38.5)
4
0.69
CN indicates cranial nerve; HMSN, hereditary motor and sensory neuropathy; MRI, magnetic resonance imaging; IAC, internal auditory canal; 370 CT, computed tomography 371 *Refer to Supplementary Table 1 for greater characterization of patients with cranial nerve imaging abnormalities 372 373
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Figures 375
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Figure 1. Nerve thickening and foraminal enlargement. Patient 8: Bilateral mastoid facial nerve canal 377
enlargement on axial view CT (A) with corresponding nerve enlargement on axial view MRI (B). 378
Bilateral foramen rotundum enlargement on coronal view CT (C) with corresponding nerve enlargement 379
on coronal view MRI (D). Bilateral foramen ovale enlargement on coronal view CT [right (E), left (G)] 380
with corresponding nerve enlargement on coronal view MRI [right (F), left (H)]. White arrows denote 381
imaging abnormality. All MRI images are non-contrast T1-weighted sequences. 382
383
384
385
386
387
388
389
390
391
392
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393
Figure 2. Abnormalities of the cranial nerve VII/VIII complex. (A) Patient 6: T1-weighted gadolinium 394
enhanced MRI demonstrating bilateral fundal internal auditory canal enhancement and slight thickening 395
in axial view (C+, on the right). Enhancement is not present prior to gadolinium administration (C-, on 396
the left). (B) Patient 7: Two consecutive T1-weighted gadolinium enhanced MRI axial slices 397
demonstrating bilateral fundal internal auditory canal enhancement. White arrows denote enhancement. 398
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402
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Supplementary Figures 403
404
Supplementary Figure 1. Flow chart demonstrating number of patients analyzed 405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
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Supplementary Table 1. Summary of patients with cranial nerve imaging abnormalities. Patient age in 426 years and sex in parentheses on left. 427
Hereditary
neuropathy diagnosis
Neuropathy phenotype Cranial nerve deficits Imaging findings
Patient 1
(45M)
HMSN
(unspecified type)
Chronic, progressive
sensorimotor deficits of
the bilateral extremities
(upper>lower)
Tongue numbness and
weakness
Brain MRI: Thickening of the left V3
trigeminal nerve
CT: Not available
Patient 2
(31F)
HNPP Bilateral upper and lower
extremity paresthesias
None Brain MRI: Enhancement of the left IAC
fundus with a corresponding filling defect
at the fundus on the T2-weighted sequence
suggestive of nerve thickening
CT: Not available
Patient 3
(75M)
HMSN
(unspecified type)
Chronic, progressive
sensorimotor deficits
leading to wheelchair
dependence
None Brain MRI: Enhancement of the right
IAC; thickening of the mastoid segment
facial nerves bilaterally
CT: Not available
Patient 4
(44M)
HNPP Chronic, progressive
sensorimotor deficits
None Brain MRI: Bilateral thickening of
cisternal trigeminal nerve on MRI;
thickening of the right cisternal
oculomotor nerve
CT: Bilateral enlargement of the foramina
rotundum and ovale
Patient 5
(63F)
HMSN
(unspecified type)
Chronic, progressive
sensorimotor deficits
requiring bilateral ankle
fusion
None Brain MRI: Thickening and enhancement
of the bilateral V2 trigeminal nerves and
bilateral mastoid segment facial nerves.
CT: Bilateral enlargement of the mastoid
facial nerve canals. Unable to assess
foramina rotundum due to unavailability
of CT coronal view
Patient 6
(21M)
HMSN1
(INF2 mutation)
Chronic, progressive
sensorimotor deficits;
ESRD requiring kidney
transplant and hearing
loss thought to be related
to INF2 mutation
Bilateral mild to profound
sensorineural hearing loss
and tinnitus
Skull base MRI: Bilateral enhancement
and thickening of the IAC fundus;
bilateral thickening of the cisternal, V2,
and V3 trigeminal nerves and of the
mastoid segment facial nerves
CT: Bilateral enlargement of foramina
rotundum, foramina ovale, and facial
nerve canals (genu through the mastoid
segment)
Patient 7
(52F)
HMSN
(unspecified type)
Chronic, progressive
sensorimotor deficits
most significant for
disequilibrium
Left tinnitus, bilateral mild
sensorineural hearing loss
(left>right)
Skull base MRI: Bilateral enhancement of
the IAC fundus; bilateral enhancement of
the facial nerve extending from the
geniculate ganglion to the greater
superficial petrosal nerve and tympanic
segment of the facial nerve.
CT: Not available
Patient 8
(18F
HMSN
(unspecified type)
Chronic, progressive
sensorimotor deficits of
the bilateral extremities
(lower>upper)
Intermittent left eye
diplopia and proptosis
Brain MRI: Bilateral thickening of V2 and
V3 trigeminal nerves and mastoid segment
facial nerves
CT: Bilateral enlargement of foramina
rotundum and ovale and mastoid facial
nerve canals
HMSN indicates hereditary motor and sensory neuropathy; EMG, Electromyography; HNPP, Hereditary Neuropathy with Liability to Pressure 428 Palsy; IAC, internal auditory canal; ESRD, end stage renal disease 429 430 431 432 433
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