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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.

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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 ccorrales@bwh.harvard.edu 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

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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

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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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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

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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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