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Vestibular impairment in Charcot-Marie-Tooth disease type 4C
  1. Herminio Pérez-Garrigues1,
  2. Rafael Sivera2,
  3. Juan Jesús Vílchez2,3,4,
  4. Carmen Espinós5,6,7,
  5. Francesc Palau5,6,8,
  6. Teresa Sevilla2,3,4
  1. 1 Departments of Otology, Valencia, Spain
  2. 2 Departments of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain
  3. 3 Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valencia, Spain
  4. 4 Department of Medicine, Ciudad Real, Spain
  5. 5 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain
  6. 6 Program on Rare and Genetic Diseases, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain
  7. 7 Department of Genetics, University of Valencia, Ciudad Real, Spain
  8. 8 School of Medicine, University of Castilla-La Mancha, Ciudad Real, Spain
  1. Correspondence to Rafael Sivera, Hospital U. i P. La Fe, Bulevar Sur s/n, 46024-Valencia, Spain; rafasivera{at}gmail.com

Abstract

Charcot-Marie-Tooth disease type 4C (CMT4C) is a hereditary neuropathy with prominent unsteadiness. The objective of the current study is to determine whether the imbalance in CMT4C is caused only by reduced proprioceptive input or if vestibular nerve involvement is an additional factor. We selected 10 CMT4C patients and 10 age-matched and sex-matched controls. We performed a comprehensive evaluation of the vestibular system, including video Head Impulse Test, bithermal caloric test, galvanic stimulation test and skull vibration-induced nystagmus test. None of the patients experienced dizziness, spontaneous or gaze-evoked nystagmus, but all had significant vestibular impairment when tested when compared to controls. Seven had completely unexcitable vestibular systems and abnormal vestibuloocular reflex. There was no correlation between the degree of vestibulopathy and age or clinical severity. Significant vestibular impairment is a consistent finding in CMT4C and is present early in disease evolution. The profound imbalance that is so disabling in these patients may result from a combination of proprioceptive loss and vestibular neuropathy, and this would modify the recommended rehabilitation strategies.

  • HMSN (CHARCOT-MARIE-TOOTH)
  • NEUROPATHY
  • VERTIGO

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Introduction

Recessive mutations of the SH3TC2 gene cause a demyelinating polyneuropathy (CMT4C, Charcot-Marie-Tooth disease type 4C) which can be quite disabling. It is usually an early-onset disease characterised by unsteadiness, distal weakness, occasional cranial nerve involvement (hearing loss, pupillary abnormalities and/or tongue atrophy), foot and spinal deformities.1

Postural imbalance is frequent in patients with polyneuropathy and has been attributed to a reduced somatosensory input, but the damage of the vestibular nerve in the neuropathic process could also be a factor. Distinguishing clinical symptoms of vestibular dysfunction in these patients can be quite challenging as they may present without prominent vertigo or dizziness, and comprehensive vestibular testing is complex and time-consuming. Vestibular neuropathy has rarely been described in acquired neuropathies, peroneal muscle atrophies and few forms of CMT.2 Recently, Poretti et al 3 found that vestibular loss was present in 60–75% of patients with different subtypes of CMT.

In our series of patients with CMT4C, we observed a profound postural imbalance exceeding what was expected for the severity of the peripheral neuropathy, and thus decided to perform an exhaustive clinical and instrumental vestibular testing.

Methods

Patients

We selected ten patients with genetically confirmed CMT4C and ten age-matched and sex-matched controls. The study protocol was approved by the Institutional Review Board of the Hospital U. i P. La Fe. Written informed consents were obtained from all participants.

Clinical evaluation

Subjects were questioned regarding general neuropathic and vestibular symptoms including age of independent walking, symptom onset, dizziness, unsteadiness worsened by darkness and instability of the visual environment. The neurologic assessments involved a complete neuromuscular evaluation and the CMT neuropathy score (CMTNS). The neurotological examination included the vestibule ocular reflex (VOR), evaluation of positional nystagmus with Hallpike manoeuvre and clinical examination of posture and gait with Romberg and Unterberger tests. The most recent neurophysiological data was recorded retrospectively.

Neurotological study

The studies performed were the video Head Impulse Test (vHIT), bithermal caloric test (BCT), galvanic stimulation test (GST) and skull vibration-induced nystagmus test (SVINT). The BCT, GST and SVINT were recorded with videonystagmography in a video based system, SYNAPSIS.

The vHIT was performed with a video system (GN Otometrics). The parameters evaluated were the VOR mean gain and the appearance of refixation saccades (RS), being abnormal if gain was <0.8 or there were RS. The BCT was performed by irrigating the external ear canal with cold (30°C), warm (44°C) and ice water, then recording the maximum velocity of the slow-phase component of nystagmus. The GST was performed with a galvanic stimulator device built by Maastrich Instruments and the SVINT using the V.VIB 3F stimulator (Synapsys, France). A response was considered when stimulation produced a reproducible, sustained nystagmus.

Agreeing with Zingler et al,4 we considered: complete bilateral vestibulopathy if pathological vHIT and bilateral absence of caloric responses, and incomplete bilateral vestibulopathy if reduced BCT responses (<5o/sec) and/or bilateral pathological vHIT.

Statistical analysis

Statistical analysis was performed with SPSS V.19 and included unpaired two-tailed t test for case–control mean analysis, and linear regression to compare the degree of vestibulopathy with age or clinical severity. A level of significance of 0.05 was adopted.

Results

The most relevant genetic, clinical and electrophysiological features are summarised in table 1. The series consisted of six women and four men with a mean age of 31 years, and a mean duration of the disease of 15.7 years. All were of Gypsy ethnicity except patients 4 and 8 who were Caucasian. Three subjects admitted hearing loss, none reported dizziness, but all described unsteadiness worsened by darkness. None presented spontaneous or gaze-evoked nystagmus, but correcting saccades following Halmagyi-Curthoys head impulses were observed in all patients except two. All were extremely unstable and would have fallen (except patient 9) with feet together and closed eyes. None were taking drugs which might interfere with the tests.

Table 1

Clinical characteristics and nerve conduction studies

Neurotological study

The results of the neurotologic tests are recorded in table 2. Taking all into account 7/10 patients suffered from a complete bilateral vestibular loss and the 3 remaining patients exhibited incomplete vestibulopathy. All the controls had normal vestibular function. The comparison between the group of CMT4C patients and controls revealed statistically significant differences in all the vestibular tests employed. All correlation analyses between vestibular dysfunction and age or clinical severity were clearly non-significant.

Table 2

Neurotological studies in patients and comparison to control group

Discussion

One of the hallmarks of CMT4C is the presence of unsteadiness and gait instability, which represent early and disabling symptoms. These features have generally been explained by the important sensory loss inherent to this type of CMT, but the presence and relevance of vestibular dysfunction remain unidentified.

Neuropathies of the vestibular nerve have been described in very few patients with diverse subtypes of CMT, and this is the first in depth characterisation of vestibulopathy in a CMT subtype. Our results confirm the presence of significant vestibular impairment in all CMT4C patients tested when compared to age-matched and sex-matched controls. The degree of vestibulopathy is strikingly profound in most cases, but ranges from unexcitable vestibular systems (70%), to a dysfunction expressed exclusively by the presence of refixation saccades in vHIT and the absence of response to SVINT (patient 5). The extent of vestibular dysfunction does not seem to correlate with age and appears early in the disease evolution. We could not find correlation between vestibulopathy and severity expressed by CMTNS; however, this may be partly due to limitations regarding the scale. No clinical or instrumental difference between the Gypsy and the Caucasian patients was noted.

None of our patients had positive vestibular signs (dizziness, nystagmus, etc), and only two referred difficulty in visual fixation. This may be the result of the early and gradual occurrence of the disorder, allowing for the development of mechanisms that compensate the altered vestibular inputs. In any case vestibulopathy is a consistent phenotypic feature of CMT4C in our series, and in keeping with the basic disease process is most likely due to a neuropathy of the vestibular nerve.

Proprioceptive loss was also quite striking in all our patients, and we therefore speculate that the instability typical in CMT4C may result from a combination of proprioceptive loss, vestibular neuropathy and to a lesser degree distal weakness. For clinical neurologists this information is quite relevant as certain vestibular rehabilitation strategies focused in the visual system can be offered to these patients.5

Acknowledgments

We thank would like to thank Itziar Llopis and Ana Anton for their collaboration.

References

Footnotes

  • Contributors HPG: acquisition, analysis and interpretation of data, manuscript revision. RS: analysis and interpretation of data, manuscript elaboration. JJV: critical revision of the manuscript for important intellectual content. CE: genetic screening. FP: critical revision of the manuscript for important intellectual content. TS: study concept and design, manuscript revision.

  • Funding This collaborative joint project was awarded by IRDiRC and funded by the Instituto de Salud Carlos III (ISCIII) Subdirección General de Evaluación y Fomento de la Investigación within the framework of the National R+D+I Plan [Grants no IR11/TREAT-CMT, PI12/00946 and P12/00453], co-funded with FEDER funds and the Generalitat Valenciana [grant no. Prometeo/2009/051]. The Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) and the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) are initiatives from the ISCIII.

  • Competing interests JJV received research support from the CIBERNED. FP is funded by grants from the Generalitat Valenciana (Prometeo/2009/051), the IRDiRC (IR11/TREAT-CMT) and the CIBERER. CE has a “Miguel Servet” contract funded by the ISCIII and the CIBERER and is funded by grants from the ISCIII (P12/00453) and IRDiRC (IR11/TREAT-CMT). TS is funded by grants from the IRDiRC (IR11/TREAT-CMT) and Fondo de Investigacion Sanitaria (PI12/00946).

  • Patient consent Obtained.

  • Ethics approval Institutional Review Board of the Hospital Univesitari i Politécnic La Fe, Valencia.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • HP-G and RS contributed equally to this work.