Share

September 16, 2014; 83 (12) Article

Bulbar muscle MRI changes in patients with SMA with reduced mouth opening and dysphagia

Renske I. Wadman, H. Willemijn van Bruggen, Theo D. Witkamp, Stanimira I. Sparreboom-Kalaykova, Marloes Stam, Leonard H. van den Berg, Michel H. Steenks, W. Ludo van der Pol
First published August 13, 2014, DOI: https://doi.org/10.1212/WNL.0000000000000796
Full PDF
Citation
Permissions

Make Comment

See Comments

Downloads
361

Share

Abstract

Objective: We performed a study in patients with proximal spinal muscular atrophy (SMA) to determine the prevalence of reduced maximal mouth opening (MMO) and its association with dysphagia as a reflection of bulbar dysfunction and visualized the underlying mechanisms using MRI.

Methods: We performed a cross-sectional study of MMO in 145 patients with SMA types 1–4 and 119 healthy controls and used MRI in 12 patients to visualize mandibular condylar shape and sliding and the anatomy of muscle groups relevant for mouth opening and closing. We analyzed associations of reduced MMO with SMA severity and complaints of dysphagia.

Results: Reduced MMO was defined as an interincisal distance ≤35 mm and was found in none of the healthy controls and in 100%, 79%, 50%, and 7% of patients with SMA types 1, 2, 3a, and 3b/4, respectively. MRI showed severe fatty degeneration of the lateral pterygoid muscles that mediate mouth opening by allowing mandibular condylar sliding but relatively mild involvement of the mouth closing muscles in patients with reduced MMO. Reduced MMO was associated with SMA type, age, muscle weakness, and dysphagia (p < 0.05).

Conclusions: Reduced MMO is common in SMA types 1–3a and is mainly caused by fatty degeneration of specific mouth opening muscles. Reduced MMO is a sign of bulbar dysfunction in SMA.

GLOSSARY

AUC=
area under the curve;
HFMSE=
Hammersmith Functional Motor Scale Expanded;
MMO=
maximal mouth opening;
MRC=
Medical Research Council;
PV=
predictive value;
ROC=
receiver operating characteristic;
SMA=
spinal muscular atrophy;
SMN=
survival motor neuron;
TMJ=
temporomandibular joint;
VFSS=
videofluoroscopic swallowing study

Hereditary proximal spinal muscular atrophy (SMA) is an important genetic cause of mortality in infants with early-onset SMA and leads to significant disability in children and adults with later onset of disease. SMA is caused by homozygous deletion of the survival motor neuron (SMN) 1 gene and is characterized by progressive predominantly proximal muscle weakness.1 Degeneration of the alpha motor neurons in the spinal cord is the classic pathologic hallmark of SMA. There is large variation in SMA severity, which is reflected by the distinction of SMA types 1–4.2,–,6

Involvement of the motor nuclei of the brainstem in SMA has been found in postmortem studies7,–,9 and is suggested by the frequent finding of fasciculations in the tongue, dysphagia, and several other often-reported complaints by patients.5,10,–,12 Feeding problems were mentioned by more than a third of the patients with SMA type 2 in one survey,10 and additional problems with mouth opening, biting, and chewing that may further complicate eating have also been documented.10,11,13,–,15 Dysphagia in SMA is probably caused by combined weakness of specific bulbar muscle groups and neck extensors.13,15 Limitations in mouth opening may represent a more straightforward model to study bulbar involvement in SMA.

We therefore investigated maximal mouth opening (MMO) in 145 patients with SMA types 1–4 and 119 healthy controls and visualized structural changes of bulbar muscle groups and temporomandibular joint (TMJ) morphology and dynamics in 12 patients with SMA types 2–4 with MRI.

METHODS

Patients and clinical assessment.

We performed a cross-sectional study between July 2010 and July 2013 in 145 patients with a genetically confirmed diagnosis of SMA. All patients visited the outpatient clinic of the University Medical Center Utrecht. The presence of homozygous SMN1 deletion was confirmed in all patients using multiplex ligation-dependent probe amplification (SALSA MLPA kit P060 version B2; MRC-Holland, Amsterdam, the Netherlands).

We documented medical history using National Institute of Neurological Disorders and Stroke common data element guidelines (www.commondataelements.ninds.nih.gov) and difficulties with eating, dysphagia, or choking using a semi-structured systematic questionnaire from previous studies10,11 (appendix e-1 on the Neurology® Web site at Neurology.org). We defined eating problems as frequent difficulties with biting, swallowing, and/or chewing. Dysphagia was defined as frequently occurring problems with swallowing, i.e., problems moving food or fluids from the oral cavity to the throat or delayed passage of food or drinks through the esophagus. We defined choking as frequent blockage of the throat by food or drinks.

We assessed MMO by measuring the interincisal distance between the upper and lower front teeth at the mesioincisal angles with a ruler in all 145 patients and in 119 consecutive healthy controls recruited through Dutch primary and secondary schools and the College of Dental Sciences.15 Two of the investigators (R.I.W. and H.W.v.B.) instructed and verbally stimulated participants to open their mouth as far as possible without pain.

We used age at onset and achieved motor milestones to define SMA types according to the diagnostic criteria defined by the SMA Consortium.2,–,4 The definition of SMA type 1 was an onset before the age of 6 months and inability to sit independently. Patients with SMA type 2 had onset between the ages of 6 and 18 months and had learned to sit or even briefly stand but not to walk independently. Patients with SMA type 3 developed weakness after the age of 18 months and had learned to walk independently at some stage in life. Patients with type 3 and an onset before 3 years were classified as “type 3a,” whereas patients with an onset after the age of 3 years were classified as “type 3b.”3 Finally, SMA type 4 was defined by an onset after the age of 30 years in ambulatory patients.3 In case there was a discrepancy between age at onset and achieved motor milestones, the latter was used to define SMA type.

One of the investigators (R.I.W.) assessed strength and motor function. We used the Medical Research Council (MRC) scale to document muscle strength of neck flexors and extensors; deltoids; biceps; triceps; wrist flexors and extensors; finger flexors, extensors, and spreaders; illiopsoas; gluteus maximus and medius; hamstrings; quadriceps; adductors; tibialis anterior; and plantar flexors of the feet in patients aged 5 years and older. The muscle sum score ranged between 34 and 170 (MRC 0 and MRC 1 were combined and given a score of MRC 1). We used the Hammersmith Functional Motor Scale Expanded (HFMSE) to score motor function in all patients.16,17 The intrarater test-retest variability showed a mean difference of 0.4 points (SD 2.7; SE 0.9; 95% confidence interval −1.9 to 2.65).

MRI of the temporomandibular joint and associated muscles.

MRI (Philips Achieva 3T, SENSE Head 8-channel, Best, the Netherlands) of the TMJ, muscle groups involved in mouth opening (lateral pterygoid muscle, anterior belly of the digastric muscle, geniohyoid muscle) and mouth closing (masseter muscle, temporalis muscle, medial pterygoid muscle), and the neck extensors was performed in 12 adult patients with SMA type 2–4 and a 25-year-old healthy control. Patients were recruited from 47 eligible adults without exclusion criteria for MRI (i.e., signs of nocturnal hypoventilation, severe swallowing difficulties, >15% forced vital capacity postural change between sitting and supine, presence of MRI-incompatible spinal rod fixation material) who were asked by letter whether they were interested in participating.

T1-weighted and T2-weighted images with a slice thickness of 3 mm were generated in the transverse and (oblique) sagittal planes. TMJ anatomy and dynamics, e.g., condylar shape and sliding of the mandibular condyle relative to the articular tubercle, were investigated in oblique sagittal images perpendicular to the long axis of the condyles for each joint in closed and open mouth positions. The latter position was maintained by means of a Perspex bite block between the incisors.

A radiologist (T.D.W.) and a dental specialist (M.H.S.) who were blinded to patient characteristics independently scored the images (Cohen κ between investigators = 0.8). Disagreement between scores was resolved by reaching consensus. Fatty muscle degeneration was graded on a 4-point scale (1 = normal; 2 = mild atrophy or fatty infiltration; 3 = severe atrophy or fatty infiltration; 4 = complete atrophy or fatty infiltration).18 Condylar shape and condylar sliding were scored as normal or abnormal. Condylar sliding was assessed as abnormal when the mandibular condyle did not protrude to or beyond the crest of the articular eminence in the open mouth position.

Standard protocol approvals, registrations, and patient consents.

The Medical Ethical Committee of the University Medical Center Utrecht approved the research protocol. All patients and parents of patients younger than 18 years gave informed consent prior to inclusion. This study was registered at the Central Committee on Research Involving Human Subjects, the Dutch registry for clinical trials.

Statistics.

We tested normality with the Kolmorogov-Smirnov and Shapiro–Wilk test. Disease duration and the age at inclusion had a very high correlation (r = 0.94). Therefore, multivariate analyses were checked and corrected for colinearity. We considered p values <0.05 to be significant. Correlations were analyzed using Spearman ρ. Comparisons of clinical characteristics (e.g., age, disease duration, MRC sum score, HFMSE, MMO, presence of dysphagia) between SMA types were performed using Kruskal–Wallis or Mann–Whitney U test (continuous data) or χ2/Fisher exact analysis (dichotomous data). Univariate and multivariate tests including dichotomous data were performed using (binary or multinomial) logistic regression. Multivariate analyses were performed with items that showed significant associations in univariate analysis. Receiver operating characteristic (ROC) curves were generated to analyze the predictive value of clinical motor scores and MMO for the presence of dysphagia. We used SPSS (IBM SPSS Statistics version 19, Chicago, IL) for statistical analysis.

RESULTS

Patient characteristics.

Patient characteristics are summarized in table 1. Thirty-five percent of patients reported dysphagia or choking (table 1). The majority of patients reported that they tried to prevent dysphagia and choking by changing the consistency of their food or posture during mealtimes.12,14 Sixteen patients (14%) out of 115 patients with SMA types 1–3a had a history of recurrent choking. Six (4%) patients (3 type 1, 1 type 2, 1 type 3a, and 1 type 3b) used a nasogastric- feeding tube and 13 patients (9%) with SMA types 1 and 2 had a percutaneous endoscopic gastrostomy.

View this table:
Table 1

Patient characteristics

Mouth opening.

All healthy controls had MMO of >35 mm, so reduced MMO was defined as ≤ 35 mm (table e-1). MMO was reduced in 57% of all patients and 100%, 79%, 50%, and 7% of patients with SMA types 1, 2, 3a, and 3b/4, respectively (table 1). MMO differed between SMA types (p < 0.01). These differences between SMA types were apparent from an early age (figure 1). MMO declined with age and disease duration in patients with SMA type 1 and 2 (age: correlation coefficient −0.25, p = 0.02; disease duration: correlation coefficient −0.28, p = 0.01) (figure 1).

Figure 1
Figure 1 Correlation between age and MMO

Maximal mouth opening (MMO) showed a correlation with age in patients with spinal muscular atrophy (SMA) type 1 and 2 (Spearman ρ −0.25, p = 0.02). The decline in patients with SMA type 3 with age was not significant (Spearman ρ −0.79, p = 0.56). The dotted line represents the lower limit of normal of MMO (35 mm).

MRI of TMJ and associated muscles.

MRI (figure 2, table 2 and figure e-1) showed severe to complete atrophy and fatty infiltration of the lateral pterygoid muscle, which is the most important muscle for mouth opening by mediating sliding of the mandibular condyle, in all patients with SMA type 2 and 3a who had reduced MMO. The anterior belly of the digastric muscles and geniohyoid muscles, involved in the first phase of swallowing and opening of the mouth by depressing the mandible, were moderately affected. In contrast, mouth closing muscles, i.e., the masseter and temporalis, were less affected, and the medial pterygoid muscle was relatively spared in all patients (table 2 and figure e-1). Fatty infiltration and severe atrophy of the neck extensors were present in patients with and without reduced MMO. Impaired condylar sliding occurred only in patients with mild to severe atrophy and/or fatty infiltration of lateral pterygoid muscles.

Figure 2
Figure 2 MRI of bulbar muscles in a patient with SMA and a healthy control

Representative T2-weighted MRI results of patient 3 (table 2) with spinal muscular atrophy (SMA) type 2 (panels A and B) and subject 13, a healthy control (panels C and D). Left panels (A and C) show masseter (closed arrow) and medial pterygoid muscles (dotted arrow); right panels (B and D) show lateral pterygoid muscles (arrow). Note the severe atrophy and fatty infiltration of lateral pterygoid muscles and mild abnormalities in medial pterygoid muscles and masseter in patient 3 compared to the normal aspect of all muscles in the control (subject 13).

View this table:
Table 2

MRI patient characteristics

In 2 out of 3 patients with SMA type 3b/4 and normal MMO, MRI assessment did not show any abnormality of the muscles involved in mouth opening or closing, whereas the MRI of the third patient showed mild fatty infiltration of the lateral pterygoid mucles (figure e-1).

Association of limited MMO with dysphagia, eating problems, and choking.

The presence of fasciculations in the tongue, dysphagia, eating problems, or choking events and characteristics associated with disease severity, including SMA type, age at onset, MRC score of the neck flexors and extensors, and HFMSE and MRC sum scores, correlated with MMO in univariate analysis (all p < 0.05). Dysphagia was associated with muscle weakness of the neck muscles (log regression p < 0.001). Multivariate analyses showed that limited MMO (p = 0.01) and lower MRC sum score (p = 0.01) in SMA types 1 and 2 were determinants of dysphagia. ROC analysis showed fair predictive value (PV) of the presence of dysphagia for reduced MMO (area under the curve [AUC] 0.71) or MRC sum score (AUC 0.77) and good PV for HFMSE (AUC 0.81) (figure 3).

Figure 3
Figure 3 Prediction of presence of dysphagia

Receiver operating characteristic curves of clinical scores (Medical Research Council [MRC] score, Hammersmith Functional Motor Scale Expanded [HFMSE], and maximal mouth opening [MMO]) reflecting their respective predictive values for the presence of dysphagia. HFMSE area under the curve (AUC) 0.81, MRC sum score AUC 0.77, and MMO AUC 0.71. Cutoff value for reduced MMO was set at 35 mm.

DISCUSSION

Reduced MMO is a common complication in patients with SMA, in particular those with SMA types 1 and 2. MRI of bulbar muscles in 12 patients showed that reduced MMO is caused by impaired condylar sliding due to severe fatty degeneration of the lateral pterygoid muscles with relative sparing of muscles that mediate mouth closing. Reduced MMO is associated with self-reported chewing difficulties, frequent choking, and dysphagia, suggesting that it may reflect a more general process of bulbar motor neuron degeneration in patients with SMA.

Few studies have investigated the cause and impact of dysfunction of bulbar muscles in patients with SMA.7,–,11,14 Evidence for the involvement of bulbar motor neurons comes from clinical and pathologic observations, e.g., the frequent finding of fasciculations in the tongue and postmortem studies that showed degeneration of motor nuclei in the brainstem of severely affected patients.7,–,9 Furthermore, several surveys reported a high frequency of feeding difficulties and dysphagia.10,11,14 The current view is that weakness of both bulbar and neck extensor muscles contributes to the multifactorial complication of dysphagia.10,–,15 This is compatible with the pattern of fatty degeneration of the anterior digastric, geniohyoid, and neck muscles on the MRI scans of our patients. Mouth opening and closing are mediated by a relatively limited number of muscle groups compared to swallowing, and limitations in mouth opening may therefore more accurately reflect involvement of bulbar motor nuclei in SMA pathogenesis than dysphagia.

Strengths of this study are the large number of patients of all ages encompassing nearly the full clinical spectrum of SMA, the large control group, and the MRI approach. It should be noted that patients with SMA type 1 included in this study were unusual in the sense that they all survived infancy and represent a subgroup of patients with long survival, as reported previously.3,19,–,22 We used a strict definition of reduced MMO (i.e., ≤35 mm) based on the MMO range in 119 healthy Dutch individuals, which virtually precludes the possibility that we overestimated prevalence of reduced MMO. Similar definitions for healthy individuals (varying between 40 and 44 mm for men, 38 and 42 mm for women, and 35 and 38 mm for children) were used in previous studies.23,–,25 Our prevalence figure of reduced MMO is nevertheless higher than those reported in previous studies. Limitations in mouth opening were self-reported by only 30% of Italian patients with SMA type 2 and 11% of Taiwanese patients with SMA types 2 and 3.10,11 Many Dutch patients were not aware that they had a significantly reduced MMO, which implies that previous self-reporting surveys may have underestimated the true prevalence. This may be partially explained by gradual adaptation to slow progression. Progression of MMO limitations is suggested by the correlation of reduced MMO with advancing age and longer disease duration, but this should be established in longitudinal studies.

MRI is a useful technique to document specific patterns of fatty degeneration and atrophy in myopathies and other neuromuscular disorders, and yields sufficient anatomical detail of the TMJ.26 In patients with reduced MMO, MRI showed normal condylar shape but impaired condylar sliding and marked fatty degeneration and atrophy of the lateral pterygoid muscles. Muscles that mediate mouth closing, i.e., the masseter, temporalis, and medial pterygoid muscles, and muscle groups besides the lateral pterygoid muscles that mediate mouth opening, i.e., the anterior digastric and geniohyoid muscles, were relatively spared. This pattern explains the reduction in mandibular protrusion, laterotrusion, and maximum opening of the jaw that was previously reported in patients with SMA.13,15 Normal MMO is achieved through a combination of rotation mediated by the submandibular muscles, which allows the first 20–30 mm of mouth opening, and condylar sliding that in combination with further rotation allows for mouth opening up to 50–60 mm in healthy individuals. The lateral pterygoid muscles mediate condylar sliding and thereby horizontal mandibular movements and counteract the retrusive forces of the geniohyoid and anterior digastric muscles during mouth opening, thus allowing mouth opening beyond 25–30 mm. Fatty degeneration and atrophy of the lateral pterygoid muscles will therefore lead to reduced or total absence of condylar sliding, causing severely reduced MMO. MMO of 20 mm or less is often associated with intra-articular pathology such as adhesions. This may occur secondary to significant degeneration of the lateral pterygoid muscle, as suggested by the abnormal TMJ mobility in patients with SMA and severely reduced MMO (e.g., patients 1–3, 5–6, and 9 in table 2).

Postmortem studies showed degeneration of motor neurons in the brainstem of patients with SMA with a caudo-cranial gradient. The trigeminal motor nucleus was affected in patients with severe SMA but less than lower cranial nerve nuclei.7 The high prevalence of reduced MMO in patients with SMA suggests that motor neuron loss in the trigeminal nucleus is probably more common than reported in previous pathologic studies. We can only speculate what causes the specific pattern of bulbar muscle involvement. Differences in motor unit size might explain differences in muscle atrophy and degeneration. Alternatively, specific motor neuron pools or specific bulbar muscle groups may differ in vulnerability to SMN deficiency.

A weakness of our study is the fact that we used a questionnaire, which has been used previously in SMA studies, rather than videofluoroscopic swallowing study (VFSS) to assess the presence and severity of swallowing difficulties. Longitudinal studies using both MRI and VFSS in a larger number of patients are needed to investigate the natural history of changes in bulbar muscle composition and function in relation to MMO and dysphagia. We did not include children with SMA and therefore cannot conclude at which age muscle changes start to occur. Finally, we did not perform follow-up MRI to analyze the speed of progression of atrophy and fatty degeneration.14

Dysphagia or choking was reported by 35% of our patients with reduced MMO, figures slightly higher than in previous reports,10,11 but self-reporting may not be sufficiently sensitive to detect early symptoms of dysphagia and swallowing problems. Reduced MMO may compromise eating and interfere with maintaining body weight, oral hygiene, and dental and medical care. One of our patients (39 years of age) with an MMO of 8 mm found that intubation prior to elective surgery had become impossible. This shows that reduced MMO affects patient safety and quality of life and that efficacy of interventions that prevent progression should be investigated. A second reason why measuring MMO should be incorporated in the follow-up of patients with SMA is the finding that reduced MMO is associated with an increased risk of dysphagia and choking. ROC characteristics of MMO suggest that it may represent an easy tool to assess the risk of involvement of bulbar muscle groups and dysphagia in patients with SMA, but this needs further study.

AUTHOR CONTRIBUTIONS

R.I. Wadman: drafting the manuscript for content, including writing for content, study concept or design, analysis or interpretation of data, acquisition of data, statistical analysis. H.W. van Bruggen: drafting the manuscript for content, including writing for content, acquisition of data, analysis or interpretation of data. T.D. Witkamp: drafting the manuscript for content, including writing for content, acquisition of data. S.I. Sparreboom-Kalaykova: revising the manuscript for content, including writing for content. M. Stam: drafting the manuscript for content, including writing for content, acquisition of data. L.H. van den Berg: revising the manuscript for content, including writing for content, study concept or design, interpretation of data. M.H. Steenks: revising the manuscript for content, including writing for content, study concept or design, analysis or interpretation of data, study supervision or coordination. W.L. van der Pol: revising the manuscript for content, including writing for content, study concept or design, analysis or interpretation of data, statistical analysis, study supervision or coordination, obtaining funding.

STUDY FUNDING

This study was supported by research grants from the Prinses Beatrix Spierfonds (WAR08-24) and Stichting Spieren voor Spieren.

DISCLOSURE

R. Wadman reports no disclosures relevant to the manuscript. H. van Bruggen received research support from Duchenne Parent Project and the Cornelia Stichting. T. Witkamp, S. Sparreboom-Kalaykova, and M. Stam report no disclosures relevant to the manuscript. L. van den Berg received travel grants and consultancy fees from Baxter; serves on scientific advisory boards for Prinses Beatrix Spierfonds and Thierry Latran Foundation; serves as a consultant for and has received funding for travel from Baxter International Inc.; serves on the editorial boards of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration and Journal of Neurology, Neurosurgery and Psychiatry; and receives research support from the Prinses Beatrix Fonds, Netherlands ALS Foundation, VSB Fonds, Netherlands Organisation for Health Research and Development (Vici scheme), Adessium Foundation, and the European Union. M. Steenks received research support from Duchenne Parent Project. W. van der Pol receives research support from the Prinses Beatrix Spierfonds and Stichting Spieren voor Spieren; and received funding for travel from Baxter International Inc. Go to Neurology.org for full disclosures.

ACKNOWLEDGMENT

The authors are grateful to the patients with SMA who participated in this study and to the Dutch patient organization for neuromuscular diseases (VSN). The authors would like to thank Dr. J.H. Veldink for his useful statistical advice and suggestions.

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Supplemental data at Neurology.org

  • Received December 27, 2013.
  • Accepted in final form June 24, 2014.

REFERENCES

  1. 1.↵
    1. Lefebvre S,
    2. Burglen L,
    3. Reboullet S,
    4. et al
    . Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995;80:155–165.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Munsat TL,
    2. Davies KE
    . International SMA consortium meeting; June 26–28, 1992; Bonn, Germany. Neuromuscul Disord 1992;2:423–428.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Zerres K,
    2. Rudnik-Schoneborn S
    . Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol 1995;52:518–523.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Zerres K,
    2. Rudnik-Schoneborn S,
    3. Forrest E,
    4. Lusakowska A,
    5. Borkowska J,
    6. Hausmanowa-Petrusewicz I
    . A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients. J Neurol Sci 1997;146:67–72.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Lunn MR,
    2. Wang CH
    . Spinal muscular atrophy. Lancet 2008;371:2120–2133.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Mercuri E,
    2. Bertini E,
    3. Iannaccone ST
    . Childhood spinal muscular atrophy: controversies and challenges. Lancet Neurol 2012;11:443–452.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Byers RK,
    2. Banker BQ
    . Infantile muscular atrophy. Arch Neurol 1961;5:140–164.
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Korinthenberg R,
    2. Sauer M,
    3. Ketelsen UP,
    4. et al
    . Congenital axonal neuropathy caused by deletions in the spinal muscular atrophy region. Ann Neurol 1997;42:364–368.
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Dubowitz V
    . Chaos in classification of the spinal muscular atrophies of childhood. Neuromuscul Disord 1991;1:77–80.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Chen YS,
    2. Shih HH,
    3. Chen TH,
    4. Kuo CH,
    5. Jong YJ
    . Prevalence and risk factors for feeding and swallowing difficulties in spinal muscular atrophy types II and III. J Pediatr 2012;160:447–451.e1.
    OpenUrlPubMed
  11. 11.↵
    1. Messina S,
    2. Pane M,
    3. De Rose P,
    4. et al
    . Feeding problems and malnutrition in spinal muscular atrophy type II. Neuromuscul Disord 2008;18:389–393.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Wang CH,
    2. Finkel RS,
    3. Bertini ES,
    4. et al
    . Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol 2007;22:1027–1049.
    OpenUrlAbstract/FREE Full Text
  13. 13.↵
    1. Granger MW,
    2. Buschang PH,
    3. Throckmorton GS,
    4. Iannaccone ST
    . Masticatory muscle function in patients with spinal muscular atrophy. Am J Orthod Dentofacial Orthop 1999;115:697–702.
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. van den Engel-Hoek L,
    2. Erasmus CE,
    3. van Bruggen HW,
    4. et al
    . Dysphagia in spinal muscular atrophy type II: more than a bulbar problem? Neurology 2009;73:1787–1791.
    OpenUrlAbstract/FREE Full Text
  15. 15.↵
    1. van Bruggen HW,
    2. van den Engel-Hoek L,
    3. van der Pol WL,
    4. de Wijer A,
    5. de Groot IJ,
    6. Steenks MH
    . Impaired mandibular function in spinal muscular atrophy type II: need for early recognition. J Child Neurol 2011;26:1392–1396.
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Glanzman AM,
    2. O'Hagen JM,
    3. McDermott MP,
    4. et al
    . Validation of the Expanded Hammersmith Functional Motor Scale in spinal muscular atrophy type II and III. J Child Neurol 2011;26:1499–1507.
    OpenUrlAbstract/FREE Full Text
  17. 17.↵
    1. O'Hagen JM,
    2. Glanzman AM,
    3. McDermott MP,
    4. et al
    . An expanded version of the Hammersmith Functional Motor Scale for SMA II and III patients. Neuromuscul Disord 2007;17:693–697.
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Mercuri E,
    2. Pichiecchio A,
    3. Allsop J,
    4. Messina S,
    5. Pane M,
    6. Muntoni F
    . Muscle MRI in inherited neuromuscular disorders: past, present, and future. J Magn Reson Imaging 2007;25:433–440.
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Borkowska J,
    2. Rudnik-Schoneborn S,
    3. Hausmanowa-Petrusewicz I,
    4. Zerres K
    . Early infantile form of spinal muscular atrophy (Werdnig-Hoffmann disease) with prolonged survival. Folia Neuropathol 2002;40:19–26.
    OpenUrlPubMed
  20. 20.↵
    1. Cobben JM,
    2. Lemmink HH,
    3. Snoeck I,
    4. Barth PA,
    5. van der Lee JH,
    6. de Visser M
    . Survival in SMA type I: a prospective analysis of 34 consecutive cases. Neuromuscul Disord 2008;18:541–544.
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Petit F,
    2. Cuisset JM,
    3. Rouaix-Emery N,
    4. et al
    . Insights into genotype-phenotype correlations in spinal muscular atrophy: a retrospective study of 103 patients. Muscle Nerve 2011;43:26–30.
    OpenUrlPubMed
  22. 22.↵
    1. Rudnik-Schoneborn S,
    2. Berg C,
    3. Zerres K,
    4. et al
    . Genotype-phenotype studies in infantile spinal muscular atrophy (SMA) type I in Germany: implications for clinical trials and genetic counselling. Clin Genet 2009;76:168–178.
    OpenUrlPubMed
  23. 23.↵
    1. Hirsch C,
    2. John MT,
    3. Lautenschlager C,
    4. List T
    . Mandibular jaw movement capacity in 10-17-yr-old children and adolescents: normative values and the influence of gender, age, and temporomandibular disorders. Eur J Oral Sci 2006;114:465–470.
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Vanderas AP
    . Mandibular movements and their relationship to age and body height in children with or without clinical signs of craniomandibular dysfunction: part IV. A comparative study. ASDC J Dent Child 1992;59:338–341.
    OpenUrlPubMed
  25. 25.↵
    1. Gallagher C,
    2. Gallagher V,
    3. Whelton H,
    4. Cronin M
    . The normal range of mouth opening in an Irish population. J Oral Rehabil 2004;31:110–116.
    OpenUrlPubMed
  26. 26.↵
    1. Straub V,
    2. Carlier PG,
    3. Mercuri E
    . TREAT-NMD workshop: pattern recognition in genetic muscle diseases using muscle MRI: 25–26 February 2011, Rome, Italy. Neuromuscul Disord 2012;22(suppl 2):S42–S53.
    OpenUrlCrossRefPubMed

Letters: Rapid online correspondence

No comments have been published for this article.
Comment

REQUIREMENTS

If you are uploading a letter concerning an article:
You must have updated your disclosures within six months: http://submit.neurology.org

Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.

If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.

Submission specifications:

  • Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
  • Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
  • Submit only on articles published within 6 months of issue date.
  • Do not be redundant. Read any comments already posted on the article prior to submission.
  • Submitted comments are subject to editing and editor review prior to posting.

More guidelines and information on Disputes & Debates

Compose Comment

More information about text formats

Plain text

  • No HTML tags allowed.
  • Web page addresses and e-mail addresses turn into links automatically.
  • Lines and paragraphs break automatically.
Author Information
NOTE: The first author must also be the corresponding author of the comment.
First or given name, e.g. 'Peter'.
Your last, or family, name, e.g. 'MacMoody'.
Your email address, e.g. higgs-boson@gmail.com
Your role and/or occupation, e.g. 'Orthopedic Surgeon'.
Your organization or institution (if applicable), e.g. 'Royal Free Hospital'.
Publishing Agreement
NOTE: All authors, besides the first/corresponding author, must complete a separate Publishing Agreement Form and provide via email to the editorial office before comments can be posted.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.

Vertical Tabs

You May Also be Interested in

Back to top
Advertisement

Topics Discussed

Alert Me