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Myopathies presenting with head drop: Clinical spectrum and treatment outcomes
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Myopathies presenting with head drop: clinical spectrum and treatment outcomes Reem M. Alhammad M.D. , Elie Naddaf M.D. PII: DOI: Reference:
S0960-8966(19)31228-3 https://doi.org/10.1016/j.nmd.2019.12.001 NMD 3781
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Neuromuscular Disorders
Received date: Revised date: Accepted date:
2 July 2019 23 November 2019 9 December 2019
Please cite this article as: Reem M. Alhammad M.D. , Elie Naddaf M.D. , Myopathies presenting with head drop: clinical spectrum and treatment outcomes, Neuromuscular Disorders (2019), doi: https://doi.org/10.1016/j.nmd.2019.12.001
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Highlights
Various acquired and potentially treatable myopathies can present with head drop
Respiratory and swallowing muscle involvement is common.
Splenius capitis has the highest diagnostic yield for a muscle biopsy.
Diagnostic workup can be inconclusive in about half of patients.
About half of treated patients responded to treatment in our series.
Myopathies presenting with head drop: clinical spectrum and treatment outcomes Reem M. Alhammad, M.D., Elie Naddaf, M.D. Department of Neurology, Mayo Clinic, Rochester, MN, USA
Correspondence to: Elie Naddaf, MD E-mail: [email protected] Phone: 507-284-2120 Fax: 507-538-6012
Study funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declarations of interest: none Ethical Publication statement: We confirm that we have read the Journal‟s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Author contributions: Reem Alhammad: Study concept and design, acquisition of data, statistical analysis, interpretation of data, drafting of the manuscript, revision for intellectual content Elie Naddaf: Study concept and design, statistical analysis, interpretation of data, drafting of the manuscript, revision for intellectual content, study supervision
Abstract Dropped-head syndrome can be the presenting feature of a wide spectrum of neurological conditions. In this study, we aimed to characterize clinical characteristics and treatment outcomes of 107 patients, where head drop was the presenting or predominant clinical feature of a myopathy. Median age at presentation was 68 years. A specific diagnosis was reached in 53% of patients: Inflammatory myopathy (n=16), myopathy with rimmed vacuoles (n=10), radiationinduced myopathy (n=8), sporadic late-onset nemaline myopathy (n=7), myofibrillar myopathy (n=4), facioscapulohumeral dystrophy (n=3), inclusion body myositis (n=2), mitochondrial myopathy (n=2), scleroderma-associated myopathy (n=2), and single cases of necrotizing autoimmune myopathy, drug-induced myopathy, and B-cell chronic lymphocytic leukemiamyopathy. Splenius capitis had the highest diagnostic yield for a muscle biopsy (67%). When tested, 89% of patients had abnormal pulmonary function tests, 50% abnormal swallow evaluation, 37% abnormal electrocardiogram and 13% abnormal transthoracic echocardiogram. 23/43 (53%) treated patients responded to treatment. Patient-reported limb weakness and neck flexion weakness on physical examination were associated with good response to treatment. A wide spectrum of acquired and hereditary myopathies can present with head drop, some of which are potentially treatable. Establishing a diagnosis is crucial for timely treatment administration, screening for swallowing and cardiorespiratory involvement, and counseling regarding prognosis.
Keywords: Dropped-head syndrome, head drop, axial myopathy, neck extensor myopathy, isolated neck extensor myopathy
Abbreviations B-CLL, B-cell chronic lymphocytic leukemia; DHS, dropped-head syndrome; FSHD, facioscapulohumeral muscular dystrophy; GVHD, graft-versus-host disease; IBM, inclusion body myositis; IVIg, intravenous immunoglobulin; MEK, mitogen-activated extracellular signal regulated kinase; MFM, myofibrillar myopathy; MRV, myopathy with rimmed vacuoles; NAM, necrotizing autoimmune myopathy; NOS, not otherwise specified; SLONM, sporadic late-onset nemaline myopathy.
Introduction Dropped head syndrome (DHS) can be the presenting feature of a wide spectrum of neurological conditions affecting the central and peripheral nervous systems, and can be due to underlying neck extension weakness or dystonia. Among central disorders, DHS can be seen in patients with parkinsonism (Parkinson disease or multiple system atrophy) where it can be due to underlying dystonia, myopathy, or a combination of both.[1,2] Among neuromuscular disorders, DHS can be the presenting symptom of an underlying motor neuron disease, defect of neuromuscular transmission (including myasthenia gravis, congenital myasthenia and Lambert-Eaton myasthenic syndrome), myopathy, or rarely neuropathy such as chronic inflammatory demyelinating polyradiculoneuropathy.[3–9] Indeed, the term DHS was first introduced by Suarez and Kelly in 1992 to describe a non-inflammatory myopathy with predominant neck extensor involvement.[10] The term isolated neck extensor myopathy (INEM) was used by Katz et al to describe four patients with nonspecific muscle biopsy findings and a relatively benign course, one of which had associated mild neck flexion and shoulder abduction weakness.[11] However, evaluating patients with a myopathy presenting with DHS can be challenging for several reasons including limited available literature to guide diagnostic workup, limited access to axial muscle biopsy in some institutions, and unfamiliarity of physicians with the different types of myopathies that can present with DHS. Most importantly, there is a common presumption that myopathic DHS is frequently associated with an untreatable nonspecific myopathy, and muscle biopsy in such patients has a very low diagnostic yield. In this study, we describe a large cohort of 107 patients with DHS as the presenting or predominant clinical feature of a myopathy, aiming to identify various myopathies that can present similarly, and highlight clinical characteristics, laboratory features and treatment outcomes.
Material and methods Patient selection The study was approved by the Mayo Clinic Institutional Review Board. Patients had provided informed consent allowing their health records to be reviewed for research purposes. We searched the Mayo Clinic electronic medical records to identify adult patients with a myopathy presenting with DHS, seen in our clinics between January 1st 2000 and February 28 2018. DHS was defined as limited ability to maintain an erect neck posture leading to intermittent or constant forward head drooping, with clinically appreciable weakness of neck extensors and correction of the head drop by passive extension of the neck or in recumbent position. To identify these patients, we used the following search terms: head drop, dropped head, neck extensor myopathy, or neck extensor weakness. We excluded patients with a primary diagnosis of motor neuron disease, defect of neuromuscular transmission, or a movement disorder such as parkinsonism or dystonia. We only included patients having the following features: 1) a clinically-determined myopathy confirmed by electrodiagnostic testing; 2) DHS as the first or predominant manifestation of the myopathy at onset. To be considered a predominant manifestation, the patient has to be able to ambulate independently and without any assistance or device at time of the development of the head drop. We reviewed patients‟ demographic and clinical characteristics; serological, electrodiagnostic, histopathological, and molecular data; and the results of pulmonary function tests, overnight oximetry, electrocardiogram, echocardiogram and swallow studies. In this study, we considered the following muscles to be axial: cervical, thoracic and lumbosacral paraspinal muscles, as well
as trapezius, anterior neck muscles, and abdominal muscles. Treatment response was determined by improvement on manual strength examination. Statistical analysis We carried out statistical analysis using JMP® Pro 14.1.0 (SAS Institute Inc.) statistical software. The Fischer Exact test/Chi square test and the Wilcoxon Rank Sum/Kruskal Wallis tests were used to compare categorical and continuous variables, respectively. Univariate logistic regression was performed to determine variables predicting good response to treatment. RESULTS Patient and clinical characteristics We identified 107 myopathy patients with head drop as a predominant feature. Head drop was the first or presenting manifestation of the myopathy in 92 (86%) patients. Diagnostic work up was conclusive in 57 patients (53%). A specific diagnosis was not reached in 50 patients (47%) who were labelled as having a myopathy not otherwise specified (NOS). Among these 50 patients, 21 had limited work up with no muscle biopsy or genetic testing performed. In the remaining 29 patients, at least a muscle biopsy was performed before diagnosing the patient with myopathy NOS. Baseline demographic and clinical characteristics are shown in Table 1. The 16 patients with inflammatory myopathy included: seven with inflammatory myopathy not otherwise specified, two of them with auto-aggressive features on muscle biopsy; myositis associated with connective tissue disorders in four patients, two of them with scleroderma; granulomatous myositis in two patients, one of them with systemic manifestations consistent with sarcoidosis; one with dermatomyositis; one with graft-versus-host disease in the setting of allogeneic stem cell transplant for acute myeloid leukemia; and one with myositis associated with acetylcholine receptor antibody-positive myasthenia gravis. Additional two patients had a
scleroderma-associated myopathy with no evidence of myositis on muscle biopsy (total of 4 scleroderma paitents). While both inclusion body myositis (IBM) patients had pathologicallydefined IBM, neither of them had characteristic distribution of weakness.[12] One patient had positive cytosolic 5‟nucleotidase -1A antibodies. Among genetically-determined myopathies, a specific genetic diagnosis was established in four patients: three with FSHD and one with a mitochondrial myopathy. The patient with a mitochondrial myopathy had at least a 4.5 kb mitochondrial DNA deletion (m9000-13500) involving MTATP6, MT-CO3, MT-TG, MT-ND3, MT-TR, MT-ND4L, MT-ND4, MT-TH, MTTS2, MT-TL2, and MT-ND5 genes. The other patients with a possibility of a geneticallydetermined myopathy included patients with histopathological features of myofibrillar myopathy (MFM), myopathy with rimmed vacuoles (MRV), and mitochondrial myopathy. There was no mention of a family history of myopathy or DHS in any of these patients‟ records. Death in early adulthood (age 21-44) from arrhythmogenic dilated cardiomyopathy was reported in the mother and two siblings of one patient with MFM. Only one MFM and two MRV patients had genetic testing with a comprehensive myopathy gene panel via next generation sequencing. One patient with MRV, who also had a dilated cardiomyopathy with an ejection fraction of 35%, had a likely pathogenic mutation in DSG2 (p.Glu1020Alafs*18) reported in autosomal dominant arrhythmogenic right ventricular cardiomyopathy and dilated cardiomyopathy. However, DSG2 gene is not known to be expressed in skeletal muscles. The patient with B-cell chronic lymphocytic leukemia had evidence on muscle biopsy of infiltration by immature lymphocytes. The patient with Binimetinib-induced myopathy (MEKmyopathy) developed head drop four weeks after receiving Binimetinib for metastatic melanoma which improved after discontinuing the drug. A muscle biopsy was not performed.
Among the 50 patients with myopathy NOS, a diagnosis was suspected in some patients but could not be confirmed. Three patients had a familial myopathy with DHS reported in other family members; none of them underwent further genetic testing. One patient with a history of multiple myeloma status post autologous stem cell transplant, developed his head drop while having active chronic graft-versus-host disease. A biopsy of the deltoid followed by a biopsy of the splenius capitis revealed no clear histopathological diagnosis. This could have been a graftversus-host disease-related myopathy. Another patient had a multiple myeloma with an IgG kappa monoclonal gammopathy raising suspicion for SLONM. The patient had a non-diagnostic biceps biopsy and opted not to pursue any further testing. One patient had pseudohypoparathyroidism, however the association with the DHS could not be established with certainty. We then compared the 29 myopathy NOS patients who received at least a muscle biopsy (group 1) to the 21 myopathy NOS patients who had limited work up (group 2). There was no statistically significant difference between the two groups regarding: sex, age at presentation, or duration of symptoms. 28% of patients in group 1 and 58% of patients in group 2 had weakness isolated to the axial muscles (p=0.035). There was no difference between the two groups in the percentage of patients with weakness isolated to neck extensors: 21% in group 1 and 38% in group 2 (p=0.177). Laboratory testing Laboratory testing results are summarized in Table 2. Thirteen patients had myositis antibody panel tested and was unremarkable. Electrocardiogram was abnormal in 24/65 (37%) tested patients: first-degree AV block (n=3), atrial fibrillation (n=5), atrial flutter (n=1), right bundle branch block (n=3), left bundle branch
block (n=2), long QT interval (n=2), left anterior fascicular block (n=4), nonspecific intraventricular conduction delay (n=1), combination of two or more of the above abnormalities (n=3). On echocardiography, non-ischemic cardiomyopathy was found in five out of 38 (13%) tested patients: dilated cardiomyopathy (DCM) in four patients [myopathy NOS (n = 1), MRV (n = 2), and SLONM (n = 1)] and hypertrophic cardiomyopathy (HCM) in one patient with granulomatous inflammatory myopathy. Electrodiagnostic testing Electrodiagnostic testing results are summarized in supplementary table 1. Two Hertz repetitive nerve stimulation was performed in 73 patients and was normal in all. Myokymic discharges were noted in one patient with radiation-induced myopathy. Muscle biopsies 78 patients had 94 muscle biopsies (figure 1). 26 out of 42 (62%) axial muscle biopsies were diagnostic compared to 22 out of 52 (42%) diagnostic limb muscle biopsies (p=0.058). Diagnostic yield for axial muscles was as follows: Splenius capitis with 16 diagnostic biopsies out of 24 (67%), trapezius 4/7 (57%), cervical paraspinals 5/10 (50%), and sternocleidomastoid 1/1. While for limb muscles, diagnostic yield was as follows: gluteus medius 2/4 (50%), biceps 5/11 (45%), quadriceps 4/9 (44%), triceps 3/7 (43%), deltoid 8/19 (42%), infraspinatus 0/1, and pectoralis 0/1. Among the 29 patients with myopathy NOS who had a muscle biopsy, 16 patients had only a limb muscle biopsy, 12 had only an axial muscle biopsy and one patient had a combination of one axial and one limb muscle biopsies. Treatment outcomes Data on treatment outcomes was available on 43 treated patients. The results are detailed in Table 3 and supplementary table 2. Patient-reported limb weakness and neck flexion weakness
on examination were associated with good response to treatment (Odds ratio of 4.3 and 4.9 respectively), while isolated neck extensor weakness was not associated with refractoriness to treatment. Spontaneous improvement was seen in one patient with MRV at a 15 month follow up visit with complete resolution of neck extensor weakness. To determine whether there is any selection bias in patients who were treated, we compared the same characteristics that are mentioned in Table 3 between patients who were treated versus not and found no statistically-significant difference between the two groups (data not shown). Twenty one patients required non invasive ventilatory support, mostly at night, with either CPAP or BiPAP. No patient required tube feeding. Discussion In this study, we presented the largest series of patients with a myopathy presenting with DHS. We showed a wide spectrum of acquired and hereditary conditions with such presentation, some of which are potentially treatable. We also highlighted the common respiratory and swallowing muscle involvement in these patients, which maybe further compromised from mechanical standpoint by the abnormal head posture. The diagnosis was often delayed which may have resulted in a delay in treatment. While many of these patients were referred for isolated neck extensor weakness, only 18% of patients indeed had no demonstrable weakness in other muscles upon thorough examination. Although a specific diagnosis may not be reached in every patient, and some patients may end up having an indolent course, we recommend considering a comprehensive workup in such patients. In addition to obtaining a detailed history and performing a thorough neurological evaluation, Table 4 provides detailed recommendations on the diagnostic work up of DHS. Muscle strength examination, electrodiagnostic testing and sometimes muscle MRI can guide selection of an appropriate target for a muscle biopsy.
Splenius capitis had the highest diagnostic yield in our cohort. While the work up should be tailored to the needs of each patient, we recommend obtaining a muscle biopsy from an affected muscle before diagnosing the patient with myopathy NOS. This will ensure not missing potentially-treatable conditions such as an inflammatory myopathy, the most common diagnostic category in our series. Similar to previous reports, most of these patients with inflammatory myopathy respond to treatment.[13–17] DHS can be the presenting symptom of an underlying connective tissue disorder especially scleroderma.[18,19] All four patients with a sclerodermarelated myopathy in this series responded to treatment despite detection of muscle inflammation in only two of them. Therefore, and based on previous reports, an underlying immune-mediated process is likely in scleroderma even in the absence of an inflammatory exudate on muscle biopsy.[20] It is noteworthy that myasthenia gravis can be associated with axial myositis.[21] While IBM in its classic form presents with limb weakness predominantly affecting finger flexors or the quadriceps, several atypical presentations have been described including isolated axial weakness and head drop.[12,22] In this case, patients may be misdiagnosed with inflammatory myopathy or polymyositis if histopathological evidence of protein aggregation or rimmed vacuoles is missed due to sampling error, resulting in unnecessary treatment with immunotherapy. A markedly elevated creatine kinase level should raise suspicion for a necrotizing autoimmune myopathy (NAM), and should prompt screening for statin exposure, associated HMGCR or SRP antibodies, underlying connective tissue disorder or malignancy. Yet NAM more commonly presents with diffuse weakness and only rarely is DHS the predominant presenting symptom.[23,24] Lastly among myopathies responding to immunotherapy is SLONM. These cases were included in a recently published study.[25] 21% of patients with SLONM reported a head drop as their first noted symptom and 40% had head drop
on examination upon presentation. Majority of patients respond to IVIG. Autologous stem cell transplant is an alternative treatment option in patients with a monoclonal gammopathy with suboptimal response to IVIG treatment. Therefore, we strongly recommend screening for a monoclonal gammopathy in patients presenting with DHS. However, the presence of a monoclonal gammopathy in a patient with DHS is not diagnostic of SLONM. DHS can be seen with various hematologic conditions, some of which can be associated with a monoclonal gammopathy, including B-cell chronic lymphocytic leukemia, multiple myeloma, graft-versushost disease and amyloid myopathy. Furthermore, a monoclonal gammopathy of uncertain significance is not uncommon in the general population and was seen in other disorders in this series as seen in Table 2. Based on our cohort and previously published literature, it is uncommon for genetic myopathies to present with DHS especially in adulthood. There are rare reports of myopathy presenting with DHS due to mutations in LMNA, MYH7, PABPN1 (oculopharyngeal muscular dystrophy) and SEPN1.[26–28] FSHD was the most common hereditary myopathy in our cohort, and can present with DHS, camptocormia or both.[29] Among metabolic myopathies presenting with DHS, reports of patients with mitochondrial histochemical abnormalities on muscle biopsy without identified gene defects have been previously published.[1,30] However, establishing the diagnosis of a mitochondrial myopathy on histologic grounds with no identified genetic defect can be challenging as mild mitochondrial abnormalities are not uncommon in paraspinal muscles in the normal population, and can also be seen in inflammatory myopathies especially cytochrome C oxidase negative fibers in IBM.[31] Although not represented in our cohort, myopathies due to defects in lipid metabolism can present with DHS as well.[32,33]
Additional diagnostic categories in this cohort included patients with histopathological features of MFM or MRV with no identified underlying genetic defect in patients who underwent genetic testing. Rimmed vacuoles are usually a sign of disrupted autophagy, and can be seen in a wide spectrum of hereditary and acquired myopathies. In the hereditary form, rimmed vacuoles can be the main histopathological feature of autophagic multisystem proteinopathies as seen with VCP mutations for instance.[34,35] In a previously published patient from our institution, DHS occurred at advanced stages of a VCP myopathy rather than at presentation.[36] In the acquired forms, rimmed vacuoles may be seen in inflammatory myopathies including dermatomyositis, scleroderma-myositis, or IBM. A possible underlying inflammatory myopathy may explain the response to immunotherapy in one of the patients with MRV as inflammation can be missed due to sampling error. Similar to a previously reported case, it is unclear why one patient with MRV had spontaneous resolution of his DHS.[37] A toxic or para-infectious process is possible, although there was no clear evidence in the patient‟s medical records to support this. In general, the presence of rimmed vacuoles should be interpreted with caution and should be considered as a nonspecific finding that could be associated with various acquired and genetically-determined conditions. Among medication-induced myopathies, DHS has been reported in association with MEK-inhibitors (selumetinib, binimetinib and cobimetinib) with spontaneous improvement after discontinuation of the drug, not requiring immunotherapy.[38] Hypothyroid, hyperparathyroid, and hypokalemic myopathies can also present with DHS.[39–42] As our study included a wide spectrum of potentially treatable conditions, the choice of a treatment regimen will depend on the underlying diagnosis. While every patient diagnosed with a potentially-treatable condition should be offered treatment, the decision to initiate empiric treatment for patients without a specific diagnosis or patients with MRV should be decided on a
case-by-case basis. Previous reports have described patients with myopathic DHS, normal creatine kinase level, and no detectable inflammation on muscle biopsy who responded to treatment.[43,44] Based on the findings of the current cohort, we recommend considering a treatment trial at least in patients with subacute progression of the head drop, evidence of neck flexion weakness on examination, associated connective tissue disorder, markedly elevated creatine kinase level (>1000) or active GVHD. While patient-reported limb weakness was predictive of good response to treatment, demonstrating on clinical examination that the muscle weakness is isolated to neck extensor or axial muscles did not correlate with refractoriness to treatment. However, the level of confidence in this finding is low given the small number of treated patients in this category. Limitations of this study include the retrospective study design, referral bias inherent to a tertiary care center, and lack of a uniform diagnostic approach with limited genetic work up for some patients with MFM or MRV, lack of a muscle biopsy in a proportion of patients with myopathy NOS, and lack of uniform evaluation of treatment response, with limited treatment outcome information in some patients. DHS can be the predominant feature of a wide spectrum of myopathies with inflammatory myopathy being the most common diagnostic category in our series. We highlighted the clinical characteristics, laboratory features and treatment outcomes in such patients. Establishing a diagnosis in such patients is crucial for timely treatment administration, surveillance of vital functions and counseling regarding prognosis. However, a specific diagnosis could not be established in a proportion of patients, underscoring the need for further studies to better understand the underlying pathogenesis and optimal treatment approach in patients with DHS.
Acknowledgements: The authors acknowledge all their colleagues at Mayo Clinic who contributed to the care of the patients.
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[40] Rymanowski J V., Twydell PT. Treatable dropped head syndrome in hyperparathyroidism. Muscle Nerve 2009;39:409–10. doi:10.1002/mus.21092. [41] Beekman R, Tijssen CC, Visser LH, Schellens RLLA. Dropped head as the presenting symptom of primary hyperparathyroidism. J Neurol 2002;249:1738–9. doi:10.1007/s00415-002-0898-7. [42] Taniguchi K, Okino I, Yamamoto N, Matsumoto S, Tachibana N, Hamano T. [Two cases with dropped head syndrome caused by hypokalemic myopathy]. Rinsho Shinkeigaku 2011;51:110–3. [43] Muppidi S, Saperstein DS, Shaibani A, Nations SP, Vernino S, Wolfe GI. Isolated Neck Extensor Myopathy: Is it Responsive to Immunotherapy? J Clin Neuromuscul Dis 2010;12:26–9. doi:10.1097/CND.0b013e3181d4a515. [44] Larsen H, Bogaard PW, Oppel L. A case of isolated neck extensor myopathy responding favorably to immunotherapy. J Clin Neuromuscul Dis 2013;15:73–6. doi:10.1097/CND.0000000000000015.
Figure 1: Representative muscle histopathological findings. A) Hematoxylin &Eosin-stained section from a patient with an inflammatory myopathy: large collection of inflammatory cells with a nodular appearance, surrounding perimysial blood vessels, with scattered regenerating and necrotic fibers in nearby fascicles. B) Modified trichrome-stained section from a patient with
sporadic late-onset nemaline myopathy: scattered atrophic fibers filled with nemaline rods with no inflammatory cells. C) Desmin antibody-immunoreacted section from a patient with myofibrillar myopathy: abnormal accumulation of z-disc proteins in the center of structurally abnormal fibers. D) Acid phosphatase-reacted section from a patient with inclusion body myositis: macrophages, distinguished by their markedly red cytoplasm, invading a nonnecrotic muscle fiber, surrounded by a collection of inflammatory cells. E) Modified trichrome-stained section from a patient with myopathy with rimmed vacuoles: several fibers with small vacuoles rimmed by a membraneous material. F) Succinate dehydrogenase-reacted section from a patient with mitochondrial myopathy: several fibers with subsarcolemmal accumulation of mitochondria (ragged-blue).
Table 1. Baseline demographics and symptoms at presentation Diagnosis
Total
Demographi
Patient reported symptoms
Neurological examination
cs Age
Fema
Head
Limb
Dysphag
in
le sex
drop
weakne
ia
duratio
ss
years
n in
Respirato Isolated Isolated Campto ry
neck
axial
symptom
extenso
weakne
s
r
ss
months
-cormia
Facial
Ptosis Scapul
weaknes
a
s
wingin g
weakne ss
All
107
patients
68
44
12 (1-
(42-
(41)
240)
8 (50)
18 (2-
42 (39)
30 (28)
46 (43)
19 (18)
32 (30)
15 (14)
24 (22)
12
19
(11)
(18)
88) Inflammato
16
69
ry
(49-
myopathy
83)
MRV
10
69
14 (88)
6(38)
10 (63)
1 (6)
2 (13)
3 (19)
4 (25)
0
2 (13)
2 (20)
1 (10)
5(50)
3 (30)
3 (30)
1 (10)
4 (40)
1 (10)
3 (30)
84)
1 (10)
10 (3-
(46-
72)
78) Radiation-
8
induced SLONM
63(4
2 (25)
7-77) 7
59
24 (12-
5 (63)
3 (38)
2(25)
0
2 (25)
2 (25)
1 (13)
0
1 (13)
5 (71)
4 (57)
3(43)
0
1 (14)
1 (14)
2 (29)
0
5 (71)
0
0
1 (25)
0
1 (25)
0
0
0
1(25)
1 (33)
0
0
0
1 (33)
2 (67)
2 (67)
0
1 (33)
0
1 (50)
1 (50)
0
1 (50)
0
0
0
0
108) 2 (29)
(47-
33 (572)
68) MFM
4
73
0
(58-
6 (212)
85) FSHD
3
74
1 (33)
(71-
24(648)
79) IBM
2
76 (6587)
1 (50)
7 (6-8)
Mitochondr
2
72
ial
(63-
myopathy
80)
Scleroderm
2
a-myopathy
76
0
10 (8-
0
0
1 (50)
1 (50)
1 (50)
0
1 (50)
1 (50)
0
0
2 (100)
2 (100)
0
0
1 (50)
0
1 (50)
1 (50)
1(100)
1 (100)
0
0
0
0
1 (100)
0
1
12)
1 (50)
(70-
11 (318)
81) NAM
1
48
0
24
(100) B-CLL
1
72
1
12
1 (100)
1 (100)
0
0
0
0
1 (100)
(100) MEK-
1
0
(100)
1
69
1
4
0
0
0
0
0
0
0
0
0
29
70
12
18 (2-
8 (28)
6 (21)
13(45)
6 (21)
8 (28)
2 (7)
7 (24)
6 (21)
0
(47-
(41)
240)
14
12 (1-
5 (23)
5 (24)
8 (38)
8 (38)
12 (57)
3 (14)
1 (5)
2 (9)
4 (19)
myopathy Myopathy NOS
88) Myopathy
21
75
NOS with
(47-
limited
87)
(67)
240)
workup
Continuous variables are presented as median (range), categorical variables are presented as number of patients (percentage) B-CLL, B-cell chronic lymphocytic leukemia; FSHD, facioscapulohumeral muscular dystrophy; IBM, inclusion body myositis; MFM , myofibrillar myopathy ; MRV , myopathy with rimmed vacuoles; NAM , necrotizing autoimmune myopathy; NOS, not otherwise specified; SLONM , sporadic late onset nemaline myopathy.
Table 2: Laboratory findings
Diagnosis
Total
Creatine kinase level Elevated
xULN
Serum
Abnormal
Abnormal
FVC, %
Abnormal
Oropharyngeal
monoclonal
ECG
PFT (FVC
of
overnight
dysphagia on
or MRP)
predicted
oximetry
swallow
gammopathy
evaluation
All patients
107
22/99(22)
1.4
13/72 (18)
24/65(37)
31/35 (89)
(1.1-
72 (31-
19/25 (76)
15/30 (50)
5/6 (83)
4/7 (57)
1/3 (33)
1/3 (33)
NA
2/3 (67)
115)
10) Inflammator
16
4/15 (27)
y myopathy
2.35
1/12 (8)
5/11 (45)
6/7 (86)
(1.4-
75 (4093)
4.5) MRV
10
2/10 (20)
3.1
1/7 (14)
4/14 (29)
4/4 (100)
(1.2-5) Radiation-
8
1/6 (17)
1.4
64 (3879)
2/4 (50)
0/3
1/1 (100)
31
induced SLONM
7
1/5 (20)
1.25
5/7 (71)
4/6 (67)
4/4 (100)
(1.1-
66 (35-
2/2 (100)
3/6 (50)
98)
1.4) MFM
4
1/4 (25)
1.4
1/3 (33)
1/2 (50)
NA
NA
NA
NA
FSHD
3
0/3
NA
1/3 (33)
0/3
1/1 (100)
62
2/2 (100)
NA
IBM
2
1/2 (50)
4
NA
0/1
1/1 (100)
54
0/1
1/1 (100)
Mitochondri
2
0/2
NA
0/2
0/1
0/1
91
0/1
NA
2
1/2 (50)
1.2
0/2
1/1 (100)
2/2 (100)
60 and 72
1/1 (100)
0/1
NAM
1
1/1 (100)
10
0/1
0/1
1/1 (100)
62
0/1
1/1 (100)
B-CLL
1
0/1
NA
0/1
NA
NA
NA
NA
0/1
MEK-
1
0
1
NA
0
NA
NA
NA
NA
29
5/28(18)
1.8
2/21(10)
4/12 (33)
9/10 (90)
83 (65-
4/4 (100)
2/4 (50)
al myopathy Scleroderma -myopathy
myopathy Myopathy
NOS Myopathy NOS with
(1.1-2) 21
5/19 (26)
1.3 (1.2-4)
114) 0/9
5/9 (55)
2/3 (67)
70 (60-
4/4 (100)
1/3 (33)
81)
limited workup Categorical variables are presented as number of patients/number of tested patients (percentage) B-CLL, B-cell chronic lymphocytic leukemia; FSHD, facioscapulohumeral muscular dystrophy; FVC: forced vital capacity; IBM, inclusion body myositis; MFM, myofibrillar myopathy; MRP: maximal respiratory pressures; MRV, myopathy with rimmed vacuoles; NA, not available; NAM, necrotizing autoimmune myopathy; SLONM, sporadic late-onset nemaline myopathy; xULN: times upper limit of normal
Table 3. Treatment outcomes Characteristic
P-value a
Treatment
Treatment
responsive
refractory
(n=23)
(n=20)
68 (48-87)
69 (47-87)
NS
Female
8 (40%)
9 (39%)
NS
Duration of head drop, months, median (range)
18 (2-84)
18 (2-72)
NS
Reported limb weakness
15 (65%)
6 (30%)
0.0198
Reported dysphagia
10 (43%)
4 (20%)
NS
Respiratory symptoms
12 (52%)
9 (45%)
NS
Isolated neck extension weakness
3
4
NS
Isolated axial muscle weakness
3
7
NS
14 (70%)
7 (37%)
0.0187
Age, median (range)
Neurologic examination features
Neck flexion weakness
Continuous variables are presented as median (range), categorical variables are presented as number of patients (percentage) B-CLL ,B-cell chronic lymphocytic leukemia ; FSHD, facioscapulohumeral muscular dystrophy; IBM , inclusion body myositis; MFM , myofibrillar myopathy ; MRV , myopathy with rimmed vacuoles; NAM , necrotizing autoimmune myopathy; NS, not significant; SLONM , sporadic late onset nemaline myopathy; VCP, valosin containing protein.
Table 5: Diagnostic approach to patients with myopathic dropped-head syndrome
History: Dyspnea on exertion, orthopnea, morning headaches, daytime hypersomnolence, chest pain
Comments Screening for respiratory and cardiac involvement
Dysphagia Medication list and recent toxic exposure Family history
Screening for swallowing difficulty Statins, MEK inhibitor, botulinum toxin
Prior radiation Past medical history
Muscle weakness or myopathy Paget disease, dementia, ALS (Myopathy with rimmed vacuoles) Where neck extensors in the radiation field? Special attention to hematologic and rheumatologic conditions
Physical exam Eye exam Skin exam
Joint exam Nail fold capillaroscopy Raynaud phenomenon Laboratory workup CBC
Peripheral blood smear Monoclonal protein screen
Myositis antibody panel HMGCR and SRP antibodies Lactate level TSH, PTH, calcium, potassium and phosphorus Acylcarnitine profile Cytosolic nucleatidase-1A antibody Imaging
Ocular involvement by sarcoidosis Scleroderma, dermatomyositis, sarcoidosis and GVHD can have characteristic skin lesions Evidence of inflammatory arthritis Scleroderma and other connective tissue disease Connective tissue disease Searching for signs of inflammatory and hematologic disorders Screening for B-CLL Screening for SLONM, multiple myeloma, amyloid myopathy Should include serum protein immunofixation and not only electrophoresis Dermatomyositis and other inflammatory myopathies In patients with elevated creatine kinase level Screening for a mitochondrial myopathy May also consider quantitative serum aminoacids Screening for hypokalemia, thyroid and parathyroid dysfunction Screening for lipid metabolism disorder Screening for IBM: use with caution given the high rate of false positivity with connective tissue disorders
Transthoracic echocardiogram and electrocardiogram Chest Xray
Screening for cardiac involvement
Search for underlying neoplasm Muscle MRI
Screening for interstitial lung disease or pulmonary sarcoid In inflammatory myopathies and necrotizing autoimmune myopathy May help in diagnosing hereditary myopathies or selecting a muscle to biopsy
In patients with a monoclonal gammopathy Skeletal survey Fat aspirate Congo red stain on muscle tissue Other laboratory work up Pulmonary function test with maximal respiratory pressures and overnight oximetry Swallow evaluation
Genetic testing
Screening for lytic lesions in IgG and IgA subtypes Screening for amyloid deposit Screening for amyloidosis: it should be performed routinely on all muscle biopsies
In patients with respiratory symptoms
In patients with dysphagia. Although nonspecific, pay special attention to cricopharyngeal muscle prominenance (IBM, OPMD, mitochondrial myopathy) For patients with family history, or patients with suspicion for an underlying genetic disorder (for instance joint contractures, MFM or MRV pathology); however, it can also be considered in patients with otherwise normal work up. May include one or more of the following: FSHD genetic testing OPMD genetic testing Mitochondrial DNA analysis performed on muscle tissue Myopathy gene panel by next generation sequencing including the following genes: LMNA, MYH7, SEPN1, and VCP
B-CLL, B-cell chronic lymphocytic leukemia; FSHD, facioscapulohumeral muscular dystrophy; GVHD, graft – versus – host disease; IBM, inclusion body myositis; MEK, mitogen activated kinase inhibitor; MFM, myofibrillar myopathy; MRV, myopathy with rimmed vacuoles; OPMD, oculopharyngeal muscle dystrophy ; SLONM, sporadic late onset nemaline myopathy
Myopathies presenting with head drop: clinical spectrum and treatment outcomes Reem M. Alhammad M.D. , Elie Naddaf M.D. PII: DOI: Reference:
S0960-8966(19)31228-3 https://doi.org/10.1016/j.nmd.2019.12.001 NMD 3781
To appear in:
Neuromuscular Disorders
Received date: Revised date: Accepted date:
2 July 2019 23 November 2019 9 December 2019
Please cite this article as: Reem M. Alhammad M.D. , Elie Naddaf M.D. , Myopathies presenting with head drop: clinical spectrum and treatment outcomes, Neuromuscular Disorders (2019), doi: https://doi.org/10.1016/j.nmd.2019.12.001
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Highlights
Various acquired and potentially treatable myopathies can present with head drop
Respiratory and swallowing muscle involvement is common.
Splenius capitis has the highest diagnostic yield for a muscle biopsy.
Diagnostic workup can be inconclusive in about half of patients.
About half of treated patients responded to treatment in our series.
Myopathies presenting with head drop: clinical spectrum and treatment outcomes Reem M. Alhammad, M.D., Elie Naddaf, M.D. Department of Neurology, Mayo Clinic, Rochester, MN, USA
Correspondence to: Elie Naddaf, MD E-mail: [email protected] Phone: 507-284-2120 Fax: 507-538-6012
Study funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declarations of interest: none Ethical Publication statement: We confirm that we have read the Journal‟s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Author contributions: Reem Alhammad: Study concept and design, acquisition of data, statistical analysis, interpretation of data, drafting of the manuscript, revision for intellectual content Elie Naddaf: Study concept and design, statistical analysis, interpretation of data, drafting of the manuscript, revision for intellectual content, study supervision
Abstract Dropped-head syndrome can be the presenting feature of a wide spectrum of neurological conditions. In this study, we aimed to characterize clinical characteristics and treatment outcomes of 107 patients, where head drop was the presenting or predominant clinical feature of a myopathy. Median age at presentation was 68 years. A specific diagnosis was reached in 53% of patients: Inflammatory myopathy (n=16), myopathy with rimmed vacuoles (n=10), radiationinduced myopathy (n=8), sporadic late-onset nemaline myopathy (n=7), myofibrillar myopathy (n=4), facioscapulohumeral dystrophy (n=3), inclusion body myositis (n=2), mitochondrial myopathy (n=2), scleroderma-associated myopathy (n=2), and single cases of necrotizing autoimmune myopathy, drug-induced myopathy, and B-cell chronic lymphocytic leukemiamyopathy. Splenius capitis had the highest diagnostic yield for a muscle biopsy (67%). When tested, 89% of patients had abnormal pulmonary function tests, 50% abnormal swallow evaluation, 37% abnormal electrocardiogram and 13% abnormal transthoracic echocardiogram. 23/43 (53%) treated patients responded to treatment. Patient-reported limb weakness and neck flexion weakness on physical examination were associated with good response to treatment. A wide spectrum of acquired and hereditary myopathies can present with head drop, some of which are potentially treatable. Establishing a diagnosis is crucial for timely treatment administration, screening for swallowing and cardiorespiratory involvement, and counseling regarding prognosis.
Keywords: Dropped-head syndrome, head drop, axial myopathy, neck extensor myopathy, isolated neck extensor myopathy
Abbreviations B-CLL, B-cell chronic lymphocytic leukemia; DHS, dropped-head syndrome; FSHD, facioscapulohumeral muscular dystrophy; GVHD, graft-versus-host disease; IBM, inclusion body myositis; IVIg, intravenous immunoglobulin; MEK, mitogen-activated extracellular signal regulated kinase; MFM, myofibrillar myopathy; MRV, myopathy with rimmed vacuoles; NAM, necrotizing autoimmune myopathy; NOS, not otherwise specified; SLONM, sporadic late-onset nemaline myopathy.
Introduction Dropped head syndrome (DHS) can be the presenting feature of a wide spectrum of neurological conditions affecting the central and peripheral nervous systems, and can be due to underlying neck extension weakness or dystonia. Among central disorders, DHS can be seen in patients with parkinsonism (Parkinson disease or multiple system atrophy) where it can be due to underlying dystonia, myopathy, or a combination of both.[1,2] Among neuromuscular disorders, DHS can be the presenting symptom of an underlying motor neuron disease, defect of neuromuscular transmission (including myasthenia gravis, congenital myasthenia and Lambert-Eaton myasthenic syndrome), myopathy, or rarely neuropathy such as chronic inflammatory demyelinating polyradiculoneuropathy.[3–9] Indeed, the term DHS was first introduced by Suarez and Kelly in 1992 to describe a non-inflammatory myopathy with predominant neck extensor involvement.[10] The term isolated neck extensor myopathy (INEM) was used by Katz et al to describe four patients with nonspecific muscle biopsy findings and a relatively benign course, one of which had associated mild neck flexion and shoulder abduction weakness.[11] However, evaluating patients with a myopathy presenting with DHS can be challenging for several reasons including limited available literature to guide diagnostic workup, limited access to axial muscle biopsy in some institutions, and unfamiliarity of physicians with the different types of myopathies that can present with DHS. Most importantly, there is a common presumption that myopathic DHS is frequently associated with an untreatable nonspecific myopathy, and muscle biopsy in such patients has a very low diagnostic yield. In this study, we describe a large cohort of 107 patients with DHS as the presenting or predominant clinical feature of a myopathy, aiming to identify various myopathies that can present similarly, and highlight clinical characteristics, laboratory features and treatment outcomes.
Material and methods Patient selection The study was approved by the Mayo Clinic Institutional Review Board. Patients had provided informed consent allowing their health records to be reviewed for research purposes. We searched the Mayo Clinic electronic medical records to identify adult patients with a myopathy presenting with DHS, seen in our clinics between January 1st 2000 and February 28 2018. DHS was defined as limited ability to maintain an erect neck posture leading to intermittent or constant forward head drooping, with clinically appreciable weakness of neck extensors and correction of the head drop by passive extension of the neck or in recumbent position. To identify these patients, we used the following search terms: head drop, dropped head, neck extensor myopathy, or neck extensor weakness. We excluded patients with a primary diagnosis of motor neuron disease, defect of neuromuscular transmission, or a movement disorder such as parkinsonism or dystonia. We only included patients having the following features: 1) a clinically-determined myopathy confirmed by electrodiagnostic testing; 2) DHS as the first or predominant manifestation of the myopathy at onset. To be considered a predominant manifestation, the patient has to be able to ambulate independently and without any assistance or device at time of the development of the head drop. We reviewed patients‟ demographic and clinical characteristics; serological, electrodiagnostic, histopathological, and molecular data; and the results of pulmonary function tests, overnight oximetry, electrocardiogram, echocardiogram and swallow studies. In this study, we considered the following muscles to be axial: cervical, thoracic and lumbosacral paraspinal muscles, as well
as trapezius, anterior neck muscles, and abdominal muscles. Treatment response was determined by improvement on manual strength examination. Statistical analysis We carried out statistical analysis using JMP® Pro 14.1.0 (SAS Institute Inc.) statistical software. The Fischer Exact test/Chi square test and the Wilcoxon Rank Sum/Kruskal Wallis tests were used to compare categorical and continuous variables, respectively. Univariate logistic regression was performed to determine variables predicting good response to treatment. RESULTS Patient and clinical characteristics We identified 107 myopathy patients with head drop as a predominant feature. Head drop was the first or presenting manifestation of the myopathy in 92 (86%) patients. Diagnostic work up was conclusive in 57 patients (53%). A specific diagnosis was not reached in 50 patients (47%) who were labelled as having a myopathy not otherwise specified (NOS). Among these 50 patients, 21 had limited work up with no muscle biopsy or genetic testing performed. In the remaining 29 patients, at least a muscle biopsy was performed before diagnosing the patient with myopathy NOS. Baseline demographic and clinical characteristics are shown in Table 1. The 16 patients with inflammatory myopathy included: seven with inflammatory myopathy not otherwise specified, two of them with auto-aggressive features on muscle biopsy; myositis associated with connective tissue disorders in four patients, two of them with scleroderma; granulomatous myositis in two patients, one of them with systemic manifestations consistent with sarcoidosis; one with dermatomyositis; one with graft-versus-host disease in the setting of allogeneic stem cell transplant for acute myeloid leukemia; and one with myositis associated with acetylcholine receptor antibody-positive myasthenia gravis. Additional two patients had a
scleroderma-associated myopathy with no evidence of myositis on muscle biopsy (total of 4 scleroderma paitents). While both inclusion body myositis (IBM) patients had pathologicallydefined IBM, neither of them had characteristic distribution of weakness.[12] One patient had positive cytosolic 5‟nucleotidase -1A antibodies. Among genetically-determined myopathies, a specific genetic diagnosis was established in four patients: three with FSHD and one with a mitochondrial myopathy. The patient with a mitochondrial myopathy had at least a 4.5 kb mitochondrial DNA deletion (m9000-13500) involving MTATP6, MT-CO3, MT-TG, MT-ND3, MT-TR, MT-ND4L, MT-ND4, MT-TH, MTTS2, MT-TL2, and MT-ND5 genes. The other patients with a possibility of a geneticallydetermined myopathy included patients with histopathological features of myofibrillar myopathy (MFM), myopathy with rimmed vacuoles (MRV), and mitochondrial myopathy. There was no mention of a family history of myopathy or DHS in any of these patients‟ records. Death in early adulthood (age 21-44) from arrhythmogenic dilated cardiomyopathy was reported in the mother and two siblings of one patient with MFM. Only one MFM and two MRV patients had genetic testing with a comprehensive myopathy gene panel via next generation sequencing. One patient with MRV, who also had a dilated cardiomyopathy with an ejection fraction of 35%, had a likely pathogenic mutation in DSG2 (p.Glu1020Alafs*18) reported in autosomal dominant arrhythmogenic right ventricular cardiomyopathy and dilated cardiomyopathy. However, DSG2 gene is not known to be expressed in skeletal muscles. The patient with B-cell chronic lymphocytic leukemia had evidence on muscle biopsy of infiltration by immature lymphocytes. The patient with Binimetinib-induced myopathy (MEKmyopathy) developed head drop four weeks after receiving Binimetinib for metastatic melanoma which improved after discontinuing the drug. A muscle biopsy was not performed.
Among the 50 patients with myopathy NOS, a diagnosis was suspected in some patients but could not be confirmed. Three patients had a familial myopathy with DHS reported in other family members; none of them underwent further genetic testing. One patient with a history of multiple myeloma status post autologous stem cell transplant, developed his head drop while having active chronic graft-versus-host disease. A biopsy of the deltoid followed by a biopsy of the splenius capitis revealed no clear histopathological diagnosis. This could have been a graftversus-host disease-related myopathy. Another patient had a multiple myeloma with an IgG kappa monoclonal gammopathy raising suspicion for SLONM. The patient had a non-diagnostic biceps biopsy and opted not to pursue any further testing. One patient had pseudohypoparathyroidism, however the association with the DHS could not be established with certainty. We then compared the 29 myopathy NOS patients who received at least a muscle biopsy (group 1) to the 21 myopathy NOS patients who had limited work up (group 2). There was no statistically significant difference between the two groups regarding: sex, age at presentation, or duration of symptoms. 28% of patients in group 1 and 58% of patients in group 2 had weakness isolated to the axial muscles (p=0.035). There was no difference between the two groups in the percentage of patients with weakness isolated to neck extensors: 21% in group 1 and 38% in group 2 (p=0.177). Laboratory testing Laboratory testing results are summarized in Table 2. Thirteen patients had myositis antibody panel tested and was unremarkable. Electrocardiogram was abnormal in 24/65 (37%) tested patients: first-degree AV block (n=3), atrial fibrillation (n=5), atrial flutter (n=1), right bundle branch block (n=3), left bundle branch
block (n=2), long QT interval (n=2), left anterior fascicular block (n=4), nonspecific intraventricular conduction delay (n=1), combination of two or more of the above abnormalities (n=3). On echocardiography, non-ischemic cardiomyopathy was found in five out of 38 (13%) tested patients: dilated cardiomyopathy (DCM) in four patients [myopathy NOS (n = 1), MRV (n = 2), and SLONM (n = 1)] and hypertrophic cardiomyopathy (HCM) in one patient with granulomatous inflammatory myopathy. Electrodiagnostic testing Electrodiagnostic testing results are summarized in supplementary table 1. Two Hertz repetitive nerve stimulation was performed in 73 patients and was normal in all. Myokymic discharges were noted in one patient with radiation-induced myopathy. Muscle biopsies 78 patients had 94 muscle biopsies (figure 1). 26 out of 42 (62%) axial muscle biopsies were diagnostic compared to 22 out of 52 (42%) diagnostic limb muscle biopsies (p=0.058). Diagnostic yield for axial muscles was as follows: Splenius capitis with 16 diagnostic biopsies out of 24 (67%), trapezius 4/7 (57%), cervical paraspinals 5/10 (50%), and sternocleidomastoid 1/1. While for limb muscles, diagnostic yield was as follows: gluteus medius 2/4 (50%), biceps 5/11 (45%), quadriceps 4/9 (44%), triceps 3/7 (43%), deltoid 8/19 (42%), infraspinatus 0/1, and pectoralis 0/1. Among the 29 patients with myopathy NOS who had a muscle biopsy, 16 patients had only a limb muscle biopsy, 12 had only an axial muscle biopsy and one patient had a combination of one axial and one limb muscle biopsies. Treatment outcomes Data on treatment outcomes was available on 43 treated patients. The results are detailed in Table 3 and supplementary table 2. Patient-reported limb weakness and neck flexion weakness
on examination were associated with good response to treatment (Odds ratio of 4.3 and 4.9 respectively), while isolated neck extensor weakness was not associated with refractoriness to treatment. Spontaneous improvement was seen in one patient with MRV at a 15 month follow up visit with complete resolution of neck extensor weakness. To determine whether there is any selection bias in patients who were treated, we compared the same characteristics that are mentioned in Table 3 between patients who were treated versus not and found no statistically-significant difference between the two groups (data not shown). Twenty one patients required non invasive ventilatory support, mostly at night, with either CPAP or BiPAP. No patient required tube feeding. Discussion In this study, we presented the largest series of patients with a myopathy presenting with DHS. We showed a wide spectrum of acquired and hereditary conditions with such presentation, some of which are potentially treatable. We also highlighted the common respiratory and swallowing muscle involvement in these patients, which maybe further compromised from mechanical standpoint by the abnormal head posture. The diagnosis was often delayed which may have resulted in a delay in treatment. While many of these patients were referred for isolated neck extensor weakness, only 18% of patients indeed had no demonstrable weakness in other muscles upon thorough examination. Although a specific diagnosis may not be reached in every patient, and some patients may end up having an indolent course, we recommend considering a comprehensive workup in such patients. In addition to obtaining a detailed history and performing a thorough neurological evaluation, Table 4 provides detailed recommendations on the diagnostic work up of DHS. Muscle strength examination, electrodiagnostic testing and sometimes muscle MRI can guide selection of an appropriate target for a muscle biopsy.
Splenius capitis had the highest diagnostic yield in our cohort. While the work up should be tailored to the needs of each patient, we recommend obtaining a muscle biopsy from an affected muscle before diagnosing the patient with myopathy NOS. This will ensure not missing potentially-treatable conditions such as an inflammatory myopathy, the most common diagnostic category in our series. Similar to previous reports, most of these patients with inflammatory myopathy respond to treatment.[13–17] DHS can be the presenting symptom of an underlying connective tissue disorder especially scleroderma.[18,19] All four patients with a sclerodermarelated myopathy in this series responded to treatment despite detection of muscle inflammation in only two of them. Therefore, and based on previous reports, an underlying immune-mediated process is likely in scleroderma even in the absence of an inflammatory exudate on muscle biopsy.[20] It is noteworthy that myasthenia gravis can be associated with axial myositis.[21] While IBM in its classic form presents with limb weakness predominantly affecting finger flexors or the quadriceps, several atypical presentations have been described including isolated axial weakness and head drop.[12,22] In this case, patients may be misdiagnosed with inflammatory myopathy or polymyositis if histopathological evidence of protein aggregation or rimmed vacuoles is missed due to sampling error, resulting in unnecessary treatment with immunotherapy. A markedly elevated creatine kinase level should raise suspicion for a necrotizing autoimmune myopathy (NAM), and should prompt screening for statin exposure, associated HMGCR or SRP antibodies, underlying connective tissue disorder or malignancy. Yet NAM more commonly presents with diffuse weakness and only rarely is DHS the predominant presenting symptom.[23,24] Lastly among myopathies responding to immunotherapy is SLONM. These cases were included in a recently published study.[25] 21% of patients with SLONM reported a head drop as their first noted symptom and 40% had head drop
on examination upon presentation. Majority of patients respond to IVIG. Autologous stem cell transplant is an alternative treatment option in patients with a monoclonal gammopathy with suboptimal response to IVIG treatment. Therefore, we strongly recommend screening for a monoclonal gammopathy in patients presenting with DHS. However, the presence of a monoclonal gammopathy in a patient with DHS is not diagnostic of SLONM. DHS can be seen with various hematologic conditions, some of which can be associated with a monoclonal gammopathy, including B-cell chronic lymphocytic leukemia, multiple myeloma, graft-versushost disease and amyloid myopathy. Furthermore, a monoclonal gammopathy of uncertain significance is not uncommon in the general population and was seen in other disorders in this series as seen in Table 2. Based on our cohort and previously published literature, it is uncommon for genetic myopathies to present with DHS especially in adulthood. There are rare reports of myopathy presenting with DHS due to mutations in LMNA, MYH7, PABPN1 (oculopharyngeal muscular dystrophy) and SEPN1.[26–28] FSHD was the most common hereditary myopathy in our cohort, and can present with DHS, camptocormia or both.[29] Among metabolic myopathies presenting with DHS, reports of patients with mitochondrial histochemical abnormalities on muscle biopsy without identified gene defects have been previously published.[1,30] However, establishing the diagnosis of a mitochondrial myopathy on histologic grounds with no identified genetic defect can be challenging as mild mitochondrial abnormalities are not uncommon in paraspinal muscles in the normal population, and can also be seen in inflammatory myopathies especially cytochrome C oxidase negative fibers in IBM.[31] Although not represented in our cohort, myopathies due to defects in lipid metabolism can present with DHS as well.[32,33]
Additional diagnostic categories in this cohort included patients with histopathological features of MFM or MRV with no identified underlying genetic defect in patients who underwent genetic testing. Rimmed vacuoles are usually a sign of disrupted autophagy, and can be seen in a wide spectrum of hereditary and acquired myopathies. In the hereditary form, rimmed vacuoles can be the main histopathological feature of autophagic multisystem proteinopathies as seen with VCP mutations for instance.[34,35] In a previously published patient from our institution, DHS occurred at advanced stages of a VCP myopathy rather than at presentation.[36] In the acquired forms, rimmed vacuoles may be seen in inflammatory myopathies including dermatomyositis, scleroderma-myositis, or IBM. A possible underlying inflammatory myopathy may explain the response to immunotherapy in one of the patients with MRV as inflammation can be missed due to sampling error. Similar to a previously reported case, it is unclear why one patient with MRV had spontaneous resolution of his DHS.[37] A toxic or para-infectious process is possible, although there was no clear evidence in the patient‟s medical records to support this. In general, the presence of rimmed vacuoles should be interpreted with caution and should be considered as a nonspecific finding that could be associated with various acquired and genetically-determined conditions. Among medication-induced myopathies, DHS has been reported in association with MEK-inhibitors (selumetinib, binimetinib and cobimetinib) with spontaneous improvement after discontinuation of the drug, not requiring immunotherapy.[38] Hypothyroid, hyperparathyroid, and hypokalemic myopathies can also present with DHS.[39–42] As our study included a wide spectrum of potentially treatable conditions, the choice of a treatment regimen will depend on the underlying diagnosis. While every patient diagnosed with a potentially-treatable condition should be offered treatment, the decision to initiate empiric treatment for patients without a specific diagnosis or patients with MRV should be decided on a
case-by-case basis. Previous reports have described patients with myopathic DHS, normal creatine kinase level, and no detectable inflammation on muscle biopsy who responded to treatment.[43,44] Based on the findings of the current cohort, we recommend considering a treatment trial at least in patients with subacute progression of the head drop, evidence of neck flexion weakness on examination, associated connective tissue disorder, markedly elevated creatine kinase level (>1000) or active GVHD. While patient-reported limb weakness was predictive of good response to treatment, demonstrating on clinical examination that the muscle weakness is isolated to neck extensor or axial muscles did not correlate with refractoriness to treatment. However, the level of confidence in this finding is low given the small number of treated patients in this category. Limitations of this study include the retrospective study design, referral bias inherent to a tertiary care center, and lack of a uniform diagnostic approach with limited genetic work up for some patients with MFM or MRV, lack of a muscle biopsy in a proportion of patients with myopathy NOS, and lack of uniform evaluation of treatment response, with limited treatment outcome information in some patients. DHS can be the predominant feature of a wide spectrum of myopathies with inflammatory myopathy being the most common diagnostic category in our series. We highlighted the clinical characteristics, laboratory features and treatment outcomes in such patients. Establishing a diagnosis in such patients is crucial for timely treatment administration, surveillance of vital functions and counseling regarding prognosis. However, a specific diagnosis could not be established in a proportion of patients, underscoring the need for further studies to better understand the underlying pathogenesis and optimal treatment approach in patients with DHS.
Acknowledgements: The authors acknowledge all their colleagues at Mayo Clinic who contributed to the care of the patients.
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Figure 1: Representative muscle histopathological findings. A) Hematoxylin &Eosin-stained section from a patient with an inflammatory myopathy: large collection of inflammatory cells with a nodular appearance, surrounding perimysial blood vessels, with scattered regenerating and necrotic fibers in nearby fascicles. B) Modified trichrome-stained section from a patient with
sporadic late-onset nemaline myopathy: scattered atrophic fibers filled with nemaline rods with no inflammatory cells. C) Desmin antibody-immunoreacted section from a patient with myofibrillar myopathy: abnormal accumulation of z-disc proteins in the center of structurally abnormal fibers. D) Acid phosphatase-reacted section from a patient with inclusion body myositis: macrophages, distinguished by their markedly red cytoplasm, invading a nonnecrotic muscle fiber, surrounded by a collection of inflammatory cells. E) Modified trichrome-stained section from a patient with myopathy with rimmed vacuoles: several fibers with small vacuoles rimmed by a membraneous material. F) Succinate dehydrogenase-reacted section from a patient with mitochondrial myopathy: several fibers with subsarcolemmal accumulation of mitochondria (ragged-blue).
Table 1. Baseline demographics and symptoms at presentation Diagnosis
Total
Demographi
Patient reported symptoms
Neurological examination
cs Age
Fema
Head
Limb
Dysphag
in
le sex
drop
weakne
ia
duratio
ss
years
n in
Respirato Isolated Isolated Campto ry
neck
axial
symptom
extenso
weakne
s
r
ss
months
-cormia
Facial
Ptosis Scapul
weaknes
a
s
wingin g
weakne ss
All
107
patients
68
44
12 (1-
(42-
(41)
240)
8 (50)
18 (2-
42 (39)
30 (28)
46 (43)
19 (18)
32 (30)
15 (14)
24 (22)
12
19
(11)
(18)
88) Inflammato
16
69
ry
(49-
myopathy
83)
MRV
10
69
14 (88)
6(38)
10 (63)
1 (6)
2 (13)
3 (19)
4 (25)
0
2 (13)
2 (20)
1 (10)
5(50)
3 (30)
3 (30)
1 (10)
4 (40)
1 (10)
3 (30)
84)
1 (10)
10 (3-
(46-
72)
78) Radiation-
8
induced SLONM
63(4
2 (25)
7-77) 7
59
24 (12-
5 (63)
3 (38)
2(25)
0
2 (25)
2 (25)
1 (13)
0
1 (13)
5 (71)
4 (57)
3(43)
0
1 (14)
1 (14)
2 (29)
0
5 (71)
0
0
1 (25)
0
1 (25)
0
0
0
1(25)
1 (33)
0
0
0
1 (33)
2 (67)
2 (67)
0
1 (33)
0
1 (50)
1 (50)
0
1 (50)
0
0
0
0
108) 2 (29)
(47-
33 (572)
68) MFM
4
73
0
(58-
6 (212)
85) FSHD
3
74
1 (33)
(71-
24(648)
79) IBM
2
76 (6587)
1 (50)
7 (6-8)
Mitochondr
2
72
ial
(63-
myopathy
80)
Scleroderm
2
a-myopathy
76
0
10 (8-
0
0
1 (50)
1 (50)
1 (50)
0
1 (50)
1 (50)
0
0
2 (100)
2 (100)
0
0
1 (50)
0
1 (50)
1 (50)
1(100)
1 (100)
0
0
0
0
1 (100)
0
1
12)
1 (50)
(70-
11 (318)
81) NAM
1
48
0
24
(100) B-CLL
1
72
1
12
1 (100)
1 (100)
0
0
0
0
1 (100)
(100) MEK-
1
0
(100)
1
69
1
4
0
0
0
0
0
0
0
0
0
29
70
12
18 (2-
8 (28)
6 (21)
13(45)
6 (21)
8 (28)
2 (7)
7 (24)
6 (21)
0
(47-
(41)
240)
14
12 (1-
5 (23)
5 (24)
8 (38)
8 (38)
12 (57)
3 (14)
1 (5)
2 (9)
4 (19)
myopathy Myopathy NOS
88) Myopathy
21
75
NOS with
(47-
limited
87)
(67)
240)
workup
Continuous variables are presented as median (range), categorical variables are presented as number of patients (percentage) B-CLL, B-cell chronic lymphocytic leukemia; FSHD, facioscapulohumeral muscular dystrophy; IBM, inclusion body myositis; MFM , myofibrillar myopathy ; MRV , myopathy with rimmed vacuoles; NAM , necrotizing autoimmune myopathy; NOS, not otherwise specified; SLONM , sporadic late onset nemaline myopathy.
Table 2: Laboratory findings
Diagnosis
Total
Creatine kinase level Elevated
xULN
Serum
Abnormal
Abnormal
FVC, %
Abnormal
Oropharyngeal
monoclonal
ECG
PFT (FVC
of
overnight
dysphagia on
or MRP)
predicted
oximetry
swallow
gammopathy
evaluation
All patients
107
22/99(22)
1.4
13/72 (18)
24/65(37)
31/35 (89)
(1.1-
72 (31-
19/25 (76)
15/30 (50)
5/6 (83)
4/7 (57)
1/3 (33)
1/3 (33)
NA
2/3 (67)
115)
10) Inflammator
16
4/15 (27)
y myopathy
2.35
1/12 (8)
5/11 (45)
6/7 (86)
(1.4-
75 (4093)
4.5) MRV
10
2/10 (20)
3.1
1/7 (14)
4/14 (29)
4/4 (100)
(1.2-5) Radiation-
8
1/6 (17)
1.4
64 (3879)
2/4 (50)
0/3
1/1 (100)
31
induced SLONM
7
1/5 (20)
1.25
5/7 (71)
4/6 (67)
4/4 (100)
(1.1-
66 (35-
2/2 (100)
3/6 (50)
98)
1.4) MFM
4
1/4 (25)
1.4
1/3 (33)
1/2 (50)
NA
NA
NA
NA
FSHD
3
0/3
NA
1/3 (33)
0/3
1/1 (100)
62
2/2 (100)
NA
IBM
2
1/2 (50)
4
NA
0/1
1/1 (100)
54
0/1
1/1 (100)
Mitochondri
2
0/2
NA
0/2
0/1
0/1
91
0/1
NA
2
1/2 (50)
1.2
0/2
1/1 (100)
2/2 (100)
60 and 72
1/1 (100)
0/1
NAM
1
1/1 (100)
10
0/1
0/1
1/1 (100)
62
0/1
1/1 (100)
B-CLL
1
0/1
NA
0/1
NA
NA
NA
NA
0/1
MEK-
1
0
1
NA
0
NA
NA
NA
NA
29
5/28(18)
1.8
2/21(10)
4/12 (33)
9/10 (90)
83 (65-
4/4 (100)
2/4 (50)
al myopathy Scleroderma -myopathy
myopathy Myopathy
NOS Myopathy NOS with
(1.1-2) 21
5/19 (26)
1.3 (1.2-4)
114) 0/9
5/9 (55)
2/3 (67)
70 (60-
4/4 (100)
1/3 (33)
81)
limited workup Categorical variables are presented as number of patients/number of tested patients (percentage) B-CLL, B-cell chronic lymphocytic leukemia; FSHD, facioscapulohumeral muscular dystrophy; FVC: forced vital capacity; IBM, inclusion body myositis; MFM, myofibrillar myopathy; MRP: maximal respiratory pressures; MRV, myopathy with rimmed vacuoles; NA, not available; NAM, necrotizing autoimmune myopathy; SLONM, sporadic late-onset nemaline myopathy; xULN: times upper limit of normal
Table 3. Treatment outcomes Characteristic
P-value a
Treatment
Treatment
responsive
refractory
(n=23)
(n=20)
68 (48-87)
69 (47-87)
NS
Female
8 (40%)
9 (39%)
NS
Duration of head drop, months, median (range)
18 (2-84)
18 (2-72)
NS
Reported limb weakness
15 (65%)
6 (30%)
0.0198
Reported dysphagia
10 (43%)
4 (20%)
NS
Respiratory symptoms
12 (52%)
9 (45%)
NS
Isolated neck extension weakness
3
4
NS
Isolated axial muscle weakness
3
7
NS
14 (70%)
7 (37%)
0.0187
Age, median (range)
Neurologic examination features
Neck flexion weakness
Continuous variables are presented as median (range), categorical variables are presented as number of patients (percentage) B-CLL ,B-cell chronic lymphocytic leukemia ; FSHD, facioscapulohumeral muscular dystrophy; IBM , inclusion body myositis; MFM , myofibrillar myopathy ; MRV , myopathy with rimmed vacuoles; NAM , necrotizing autoimmune myopathy; NS, not significant; SLONM , sporadic late onset nemaline myopathy; VCP, valosin containing protein.
Table 5: Diagnostic approach to patients with myopathic dropped-head syndrome
History: Dyspnea on exertion, orthopnea, morning headaches, daytime hypersomnolence, chest pain
Comments Screening for respiratory and cardiac involvement
Dysphagia Medication list and recent toxic exposure Family history
Screening for swallowing difficulty Statins, MEK inhibitor, botulinum toxin
Prior radiation Past medical history
Muscle weakness or myopathy Paget disease, dementia, ALS (Myopathy with rimmed vacuoles) Where neck extensors in the radiation field? Special attention to hematologic and rheumatologic conditions
Physical exam Eye exam Skin exam
Joint exam Nail fold capillaroscopy Raynaud phenomenon Laboratory workup CBC
Peripheral blood smear Monoclonal protein screen
Myositis antibody panel HMGCR and SRP antibodies Lactate level TSH, PTH, calcium, potassium and phosphorus Acylcarnitine profile Cytosolic nucleatidase-1A antibody Imaging
Ocular involvement by sarcoidosis Scleroderma, dermatomyositis, sarcoidosis and GVHD can have characteristic skin lesions Evidence of inflammatory arthritis Scleroderma and other connective tissue disease Connective tissue disease Searching for signs of inflammatory and hematologic disorders Screening for B-CLL Screening for SLONM, multiple myeloma, amyloid myopathy Should include serum protein immunofixation and not only electrophoresis Dermatomyositis and other inflammatory myopathies In patients with elevated creatine kinase level Screening for a mitochondrial myopathy May also consider quantitative serum aminoacids Screening for hypokalemia, thyroid and parathyroid dysfunction Screening for lipid metabolism disorder Screening for IBM: use with caution given the high rate of false positivity with connective tissue disorders
Transthoracic echocardiogram and electrocardiogram Chest Xray
Screening for cardiac involvement
Search for underlying neoplasm Muscle MRI
Screening for interstitial lung disease or pulmonary sarcoid In inflammatory myopathies and necrotizing autoimmune myopathy May help in diagnosing hereditary myopathies or selecting a muscle to biopsy
In patients with a monoclonal gammopathy Skeletal survey Fat aspirate Congo red stain on muscle tissue Other laboratory work up Pulmonary function test with maximal respiratory pressures and overnight oximetry Swallow evaluation
Genetic testing
Screening for lytic lesions in IgG and IgA subtypes Screening for amyloid deposit Screening for amyloidosis: it should be performed routinely on all muscle biopsies
In patients with respiratory symptoms
In patients with dysphagia. Although nonspecific, pay special attention to cricopharyngeal muscle prominenance (IBM, OPMD, mitochondrial myopathy) For patients with family history, or patients with suspicion for an underlying genetic disorder (for instance joint contractures, MFM or MRV pathology); however, it can also be considered in patients with otherwise normal work up. May include one or more of the following: FSHD genetic testing OPMD genetic testing Mitochondrial DNA analysis performed on muscle tissue Myopathy gene panel by next generation sequencing including the following genes: LMNA, MYH7, SEPN1, and VCP
B-CLL, B-cell chronic lymphocytic leukemia; FSHD, facioscapulohumeral muscular dystrophy; GVHD, graft – versus – host disease; IBM, inclusion body myositis; MEK, mitogen activated kinase inhibitor; MFM, myofibrillar myopathy; MRV, myopathy with rimmed vacuoles; OPMD, oculopharyngeal muscle dystrophy ; SLONM, sporadic late onset nemaline myopathy