Original Article
A study of acute muscle dysfunction with particular
reference to dengue myopathy
Rajesh Verma, Vikram V. Holla, Vijay Kumar1, Amita Jain2, Nuzhat Husain3, Kiran Preet Malhotra3,
Ravindra Kumar Garg, Hardeep Singh Malhotra, Praveen Kumar Sharma, Neeraj Kumar
Departments of Neurology, 1Plastic Surgery and 2Microbiology, King George Medical University, 3Department of
Pathology, Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
Abstract
Background: Acute myopathy is a common cause of acute motor quadriparesis which has various etiologies with different courses of
illness and prognosis depending on the cause. Understanding this diversity helps us in proper approach toward diagnosis, predicting
the prognosis, and possible complications and in improving the treatments that are being provided. This study was planned to study
the clinical, electrophysiological, and etiological profile of patients presenting with acute myopathy. We also studied how dengue‑related
acute myopathy differs from other causes and also difference between myopathy due to myositis and hypokalemia in cases of dengue.
Materials and Methods: This was a prospective, observational study involving all clinically suspected cases of acute myopathy of not
more than 4 weeks duration with raised serum creatine kinase (CK) level. They were subjected to detailed clinical evaluation along with
hematological, biochemical, microbiological, and electrophysiological studies and followed‑up for outcome at 1 and 3 months. Muscle
biopsy and histopathological examination were done in selected patients after taking informed consent. Statistical analysis was performed
by appropriate methods using SPSS version 16.0 (Chicago, IL, USA). Results: We evaluated thirty patients of acute myopathy with raised
CK level. Seventeen patients had fever, 11 had myalgia, and 5 had skin lesions. All presented with symmetric weakness, 17 (56.7%)
patients having predominantly proximal weakness, neck or truncal weakness in 6 (20%), hyporeflexia in 12 (40%), with mean Medical
Research Council (MRC) sum score of 46.67 ± 6.0. Eight (mean modified Barthel index [MBI] at presentation ‑ 15 ± 3.7) patients had
poor functional status according to MBI and 15 according to modified Rankin scale (MRS) (mean MRS score ‑ 2.5 ± 1.2). Etiology was
dengue viral infection in 14 patients; hypokalemia due to various causes other than dengue in 8; pyomyositis in 3; dermatomyositis,
polymyositis, thyrotoxicosis, systemic lupus erythematosus, and unknown etiology in one each. Only eight patients had abnormal
electrophysiology and seven among nine biopsies done were abnormal. At 1 month, 24 (80.0%) and 23 (76.7%) patients had achieved
normal MBI and MRS scores with 28 (93.3) and 27 (90%) patients, respectively, at 3 months. Dengue with hypokalemia had less myalgia,
more of hyporeflexia, and lower serum CK compared to those without hypokalemia. Conclusion: Dengue infection and hypokalemia
due to various causes are the most common causes of acute myopathy and are associated with rapid and complete recovery within
1 month. Shorter duration of illness, higher MRC sum score, better disability status at presentation, lower serum CK correlate with better
outcome. Biopsy was decisive in <20% cases; hence, it is not primary investigation in acute myopathy.
Key Words
Acute myopathy, dengue myositis, electrophysiology, muscle histopathology
For correspondence:
Prof. Rajesh Verma, Department of Neurology,
King George Medical University, Lucknow ‑ 226 003, Uttar Pradesh, India.
E‑mail: drrajeshverma32@yahoo.com
Ann Indian Acad Neurol 2017;20:13‑22
Introduction
Disorders of skeletal muscle encompass a variety of illnesses
that cause weakness, pain, and fatigue in any combination.
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DOI:
10.4103/0972-2327.199914
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How to cite this article: Verma R, Holla VV, Kumar V, Jain A,
Husain N, Malhotra KP, et al. A study of acute muscle dysfunction
with particular reference to dengue myopathy. Ann Indian Acad
Neurol 2017;20:13-22.
Received: 27‑09‑16, Revised: 30‑10‑16, Accepted: 15‑12‑16
© 2006 - 2017 Annals of Indian Academy of Neurology | Published by Wolters Kluwer - Medknow
14
Verma, et al.: Acute muscle dysfunction and dengue myopathy
Myopathy simply refers to an abnormality of the muscle
and has no other connotation. Myopathy term many a
times is used interchangeably with myositis. Myositis is
defined as inflammation of muscle, especially a voluntary
muscle, characterized by pain, tenderness, swelling, and/or
weakness.[1] Myositis implies an inflammatory disorder and is
usually reserved for disorders, in which the muscle histology
shows an inflammatory response.[2] However, histopathological
confirmation cannot be obtained in all cases despite the evidence
of muscle damage in the form of elevated muscle enzymes. The
muscle biopsy may not be done due to its invasive nature or
transient and benign nature of some myopathies not warranting
biopsy, especially in the presence of obvious cause and typical
presentation. Other investigations such as nerve conduction
studies (NCSs) and electromyography (EMG) may aid in both
confirming muscle disease as the source of weakness and also
in ruling out neurogenic causes of acute muscle dysfunction.
In such cases where there is no histopathological evidence
but there is other evidence of muscle involvement, the term
myopathy or muscle dysfunction can be used instead of
myositis.
Acute myopathy or myositis is one of the common differential
diagnoses of acute motor quadriparesis among various others.
Although myopathy usually is considered to have subacute to
chronic presentation of weeks to months, some cases may have
acute presentations in days to weeks. The clinical signs and
symptoms too differ compared to chronic myopathy in terms
of fever, myalgia, absence of atrophy, weakness distribution,
symmetry of weakness, associated symptoms such as skin
changes and joint pains.
The spectrum of acute myopathy includes various etiologies
with different pathophysiology. The different etiologies of
acute myopathy include infection, electrolyte disturbances,
autoimmune conditions, genetic disorders, medication adverse
events, and diseases of the endocrine system.[1] Pathogens
such as bacteria, fungi, parasites, and viruses may lead to
infectious cause of acute myositis with virus and bacteria
contributing most of the cases. Influenza virus is the most
common cause of benign acute myositis commonly occurring
in winters and in children.[3] Whereas in countries where
dengue is endemic, dengue‑induced acute muscle dysfunction
is one of the major causes, especially during rainy season
due to increased breeding of mosquitoes.[4] Among bacteria,
Staphylococcus aureus causing pyomyositis is one of the most
common causes presenting acute to subacute with muscle
pain, swelling, or indurations with or without weakness.[5]
Other than virus and bacteria, fungi and parasites can also
present with myositis, especially cysticercosis in muscle.
Electrolyte imbalances can also present with pure muscle
weakness ranging from acute to chronic presentations. Certain
electrolyte derangements are among the most common
causes of myopathy, the most important being deficiencies of
potassium and phosphorus. Profound electrical disturbances
without serious derangements of muscle cell composition may
be seen in disorders such as hyperkalemia and hypocalcemia.
However, most serious electrolyte disorders cause evidence of
both muscle and nerve dysfunction, especially if the evaluation
includes measurements of electrical activity, such as EMG and
nerve conduction velocity.[6]
Apart from infectious and electrolyte disturbances, acute
muscle dysfunction can occur due to endocrinopathies such
as thyrotoxicosis, hypothyroidism, pheochromocytoma,
and Cushing’s syndrome; autoimmune conditions such as
polymyositis and dermatomyositis; genetic causes such as
periodic palsies; medications; and toxins.[6‑8]
Electrodiagnostic (EDX) studies are more commonly an
extension of clinical assessment and planned based on the
clinical findings and differentials. Their main use in a case
of suspected cause of myopathy is to rule out the neural or
neuromuscular cause of weakness and to narrow down the
differentials based on some specific findings such as spontaneous
activities. NCSs mostly help in showing whether there is nerve
involvement in the form of any abnormality in sensory nerve
action potential (SNAP), prolonged distal latency or reduced
velocity in compound muscle action potential (CMAP), or
temporal dispersion or conduction block. EMG plays more
important role among EDX in a case of suspected case of
myopathy. It is more sensitive in identifying myopathic cause of
weakness. Short duration, reduced amplitude, and polyphasic
muscle unit action potentials (MUAPs) with early recruitment
and complete interference pattern suggest myopathic nature
of weakness. It can also help in narrowing differentials by the
presence of spontaneous activities such as fibrillation, positive
sharp waves, or myotonia, which are seen in select few causes
with muscle membrane irritability such as inflammatory and
toxic myopathies. The role of these studies in a case of acute
myopathy under evaluation is not well established. There
are studies that have reported EDX changes in infectious
causes such as dengue, influenza, pyomyositis; electrolyte
disturbances; and inflammatory causes.[4,9‑11] EMG may not be
needed in all cases of chronic myopathy as much information
may not be gained other than nonspecific finding of myopathic
changes or may be normal in some cases of myopathies such
as endocrine or metabolic causes. Further, other ancillary tests
such as genetic analysis may help in confirming the diagnosis
in a clinically suspected case. Or in those cases where biopsy is
anyway required for the diagnosis, EMG may not be additive
in providing information. Hence, what role does EDX and
specifically EMG play in evaluation of cases of acute myopathy
and is there any different pattern was also studied in this study.
As there is a lack of studies prospectively evaluating cases of
acute myopathy, we planned this study with the aim to evaluate
clinical profile, EDX findings, and etiological spectrum in cases
of acute myopathy. Our other aims were to study the prognosis
in the form of disability at 1 and 3 months and what baseline
factors correlated with baseline severity and good prognosis
at 1 and 3 months.
Materials and Methods
This prospective, observational study was conducted
at the Department of Neurology, King George Medical
University, Lucknow, in collaboration with the Department
of Microbiology, Plastic Surgery of King George Medical
University, Lucknow, and Department of Pathology, Dr. Ram
Manohar Lohia Institute of Medical Sciences, Lucknow. The
study subjects were enrolled from August 2013 to October 2015.
Written informed consent was obtained from every individual
Annals of Indian Academy of Neurology, Volume 20, Issue 1, January-March 2017
15
Verma, et al.: Acute muscle dysfunction and dengue myopathy
or their guardian before being enrolled in the study. The study
was approved by the Institutional Ethical Committee. Flow
diagram of the study is presented in Figure 1.
Inclusion criteria
All patients admitted to the neurology department with
symptoms of acute muscle weakness of <4 weeks duration with
raised serum creatine kinase (CK) level (above upper limit of
normal [ULN] [195 IU/L]) over the study period of August 2013
to October 2015 were included in the study.
Exclusion criteria
Patients with either NCS not consistent with muscle
disease (findings apart from reduced CMAP) or EMG suggestive
of neuropathic pattern (large amplitude long duration motor
unit action potentials with fasciculations, reduced recruitment,
or incomplete interference) were excluded from the study.
Evaluation
Detailed clinical history and physical examination were done
in all patients. The weakness was graded according to Medical
Research Council (MRC) scale. MRC sum score (MSS) was
calculated as sum of overall power at bilateral shoulder, elbow,
wrist, hip, knee, and ankle, with score of 60 being maximum
power and 0 being complete weakness. Weakness was also
labeled as either distal, proximal, or both proximal and distal
based on involvement of proximal and distal musculature.
Disability assessment was done as per modified Barthel
index (MBI) (20‑point scoring system with higher points
signifying better functional status). Baseline disability was
defined as poor functional status based on MBI ≤12.
Investigation
The laboratory investigations including complete blood
count, liver and kidney function tests, serum sodium, serum
potassium, blood sugar, and serum CK were done in all acute
myopathy cases. Serum potassium of ≤3.5 mEq/L was taken
as hypokalemia. Total leukocyte counts of <4000 cells/µl was
considered as leukopenia and >11,000 cells/µl was considered
as leukocytosis. Platelet count of <1.5 × 10 6 cells/µl was
considered as thrombocytopenia. Thyroid function test,
erythrocyte sedimentation rate (ESR), C‑reactive protein,
anti‑nuclear antibody (ANA), rheumatoid factor, and blood
culture/sensitivity were done according to the clinical scenario.
Virological studies for human influenza virus, dengue virus,
cytomegalovirus, Epstein–Barr virus, Enterovirus, human
immunodeficiency virus, hepatitis B surface antigen, and
hepatitis C virus were also done according to the clinical
settings.
Electrophysiological evaluation
NCSs and EMG of all four limbs were done using standard
techniques in all patients, which included motor studies of
bilateral ulnar, median, posterior tibial, and common peroneal
nerves and sensory studies of bilateral ulnar, median, and
sural nerves. Muscles for EMG study were selected according
to clinical scenario with at least one clinically normal and
abnormal muscle sampled. Patients whose NCS showed
prolonged distal latency, reduced conduction velocity of
CMAP, conduction block, or abnormal SNAP were excluded
from the study. The patients with large amplitude,long
duration MUAPs, fasciculations, reduced recruitment and
incomplete interference suggestive of neuropathic pattern on
Electromyography were also excluded from this study.
Muscle biopsy
Muscle biopsy was done after taking informed consent and
only in selected patients after considering the indications
and contraindications for the procedures. The procedure
was done in the Department of Plastic Surgery, King George
Medical University, under local anesthesia in sterile aseptic
condition. Two muscle tissue samples from moderately weak
muscle, preferable right vastus lateralis were collected one
sample each in a saline‑soaked gauge and sterile container
containing formalin. The samples were sent to the Department
of Pathology, Dr. Ram Manohar Lohia Institute of Medical
Sciences, on the same day of biopsy procedure for fixation and
staining. Necessary precautions were taken before, during, and
after the procedure to prevent any untoward complication.
Treatment
Standard treatment was given to every patient according to
the cause of myopathy after the initial investigations to look
for the etiology.
Follow‑up and assessment of outcome
All patients were followed up at 1 and 3 months for repeat
clinical history and physical examination along with disability
assessment as per MBI with poor outcome defined as MBI ≤12
at 1 and 3 months.
Figure 1: Plan of study
Statistical analysis
Statistical analysis was performed using the Statistical
Package of Social Sciences (SPSS) version. 16.0 (Chicago, IL,
USA). Categorical variables are expressed as percentages
and continuous variables are expressed as means ± standard
deviation. Chi‑square test or Fisher’s exact test was used to
compare qualitative variables as applicable. Independent
Annals of Indian Academy of Neurology, Volume 20, Issue 1, January-March 2017
16
Verma, et al.: Acute muscle dysfunction and dengue myopathy
sample t‑test and ANOVA were used to compare means as
applicable. Spearman’s correlation was used for correlation
coefficient. A P < 0.05 was considered statistically significant.
Results
Thirty‑two patients were included in the study based on the
predefined inclusion criteria. Two of them were excluded as
they had NCS not compatible with myopathy. The baseline
demographic, clinical features, and investigations of all thirty
patients (twenty males, ten females) are shown in Table 1. The
mean age of the study population was 29.3 ± 11.5 years, with
mean duration of symptoms being 6.4 ± 7.3 (range: 1–25) days.
Clinical features
Apart from weakness, fever (17) was the most common
associated symptom with other symptoms being muscle
pain (11), muscle swelling (2), and skin lesions (5). Weakness
was symmetrical in all with pure proximal weakness more
compared to proximal and distal weakness and five patients
had weakness of neck and truncal muscles also. Mean MSS
was 46.67 ± 6.0 ranging from 28 to 54. Hyporeflexia or areflexia
was seen in 12 patients. Eight patients had poor functional
status according to MBI. None of the patients had renal failure.
Investigations
Complete blood count revealed thrombocytopenia in 12,
leukopenia in 7, leukocytosis in 6, and relative lymphocytosis
in 10. Mean serum CK level was 3158.2 IU/L with 3–10 times
above ULN in 10 and more than 10 times in 11. Hypokalemia
was seen in 13, elevated ANA in 4, anti‑Ro in 1, thyroid function
tests suggesting hyperthyroidism in two and hypothyroidism
in one. Blood culture was positive for S. aureus in three patients
of acute bacterial myositis.
EMG showed myopathic changes in all patients with many
showing only mild myopathic changes in the form of short
to normal amplitude, short duration, polyphasic MUAPs.
Spontaneous activity in the form of fibrillation and positive
sharp waves in EMG was seen in eight patients (three cases of
pyomyositis and one each of dengue with hypokalemia, dengue
without hypokalemia, dermatomyositis, polymyositis, and
myopathy secondary to systemic lupus erythematosus [SLE]).
NCS was abnormal in only two patients showing only reduced
amplitudes of CMAPs.
Dengue infection (14 patients) was the most common etiology
with dengue nonstructural protein 1 (NS1) antigen positivity in
7 patients, IgM antibody against dengue virus in 3 patients, and
both dengue NS1 antigen and IgM antibody against dengue
in 4 patients. Hypokalemia (13 patients) was the next most
common etiology, which included five cases of dengue virus
infection, three cases of probable hypokalemic periodic palsy.
There was one case each of renal tubular acidosis, renal tubular
acidosis secondary to Sjogren’s syndrome, hyperthyroidism,
acute pancreatitis, and drug‑induced causing hypokalemia.
Other etiologies included acute bacterial myositis (3),
dermatomyositis (1), polymyositis (1), myopathy secondary
to SLE (1), hyperthyroidism without hypokalemia (1), and
unknown cause (1).
Table 1: Baseline demographic, clinical features,
disability status, and investigation profile of thirty
patients of acute myopathy
Variable
Age (years)
Sex
Male
Female
Duration of symptoms (days)
Fever
Muscle pain
Muscle swelling
Skin lesions
Weakness
Proximal only
Proximal and distal
Neck or truncal weakness
MRC sum score (0–60)
DTRs
Normal
Hyporeflexia
MBI at presentation
Good (>12)
Poor (≤12)
Total hemoglobin (gm/dl)
PCV (%)
Platelet count (×103 cells/µl)
Thrombocytopenia (<150×103
cells/µl)
Total leukocyte count (cells/µl)
Normal (4000–11,000)
Leukocytopenia (<4000)
Leukocytosis (>11,000)
Relative lymphocyte (%)
Relative lymphocytosis (>35%)
Total serum CK (IU/L)
<3 times ULN
3–10 times ULN
>10 times ULN
AST (IU/L)
ALT (IU/L)
Serum potassium (mmol/L)
Hypokalemia (<3.5 mmol/L)
TSH (µIU/ml)
Normal
Low
High
ESR (mm in 1 h)
ANA
Negative
Positive
Electrophysiology
Abnormal NCS
Myopathic EMG
Annals of Indian Academy of Neurology, Volume 20, Issue 1, January-March 2017
Mean±SD (range) or n (%)
29.3±11.5 (10-50)
20 (66.7)
10 (33.3)
6.4±7.3 (1-25)
17 (56.7)
11 (36.7)
2 (6.7)
5 (16.7)
17 (56.7)
13 (43.3)
5 (16.7)
46.67±6.0 (28-54)
18 (60)
12 (40)
15±3.7 (7-20)
22 (73.3)
8 (26.7)
12.8±1.9 (8.2-16.6)
42.6±4.9 (32.0-52.0)
183±148 (25–737)
12 (40)
8283.7±6684.8 (2700-37,480)
17 (66.7)
7 (23.3)
6 (20.0)
29.67±10.3 (10-49)
10 (33.3)
3158.2±4668.6
(240.0-18,540.0)
9 (30.0)
10 (33.3)
11 (36.7)
184.3±213.9 (18-870)
90.3±112.2 (10.6-536.0)
3.48±0.9 (1.3-5.0)
13 (43.3)
3.05±1.3 (0.05-7.0)
27 (90.0)
2 (6.7)
1 (3.3)
20.8±13.3 (9-80)
26 (86.7)
4 (13.3)
2 (6.7)
22 (73.3)
Contd...
17
Verma, et al.: Acute muscle dysfunction and dengue myopathy
Table 1: Contd...
Variable
Myopathic EMG with
spontaneous activity
Muscle biopsy
Not done
Normal
Abnormal
Etiology
Dengue with hypokalemia
Dengue without hypokalemia
Hypokalemia due to other
causes
Pyomyositis
Polymyositis/
dermatomyositis
Others
Mean±SD (range) or n (%)
8 (26.7)
24
2
4
alanine aminotransferase (ALT), serum potassium, ESR,
packed cell volume, platelet count, total leukocyte count,
and relative lymphocyte percentage. While in patients with
dengue infection, serum potassium showed significant positive
correlation with MSS (P = 0.03, r = 0.58), suggesting that lower
potassium level correlates with more severe weakness at
presentation.
Disability outcome at 1 and 3 months
Clinical outcome was assessed at 1 and 3 months by MBI. Only
one patient had full MBI score at presentation. At 1 month,
24 patients attained full MBI score while all except two attained
it by the end of 3 months. One death occurred (acute myopathy
of unknown cause) at the end of 1 month and none thereafter at
3 months follow‑up. No patients had MBI ≤12 at 1 and 3 months
follow‑up with lowest MBI of 17 at 1 month follow‑up and 18
at 3 months.
5 (16.7)
9 (30.0)
8 (26.7)
3 (10.0)
2 (6.7)
3 (10.0)
MRC = Medical Research Council, DRTs = Deep tendon reflexes,
MBI = Modified Barthel index, PCV = Packed cell volume, CK = Creatine
kinase, ULN = Upper limit of normal, AST = Aspartate aminotransferase,
ALT = Alanine transaminase, TSH = Thyroid‑stimulating hormone,
ESR = Erythrocyte sedimentation rate, ANA = Anti‑nuclear antibody,
NCS = Nerve conduction studies, EMG = Electromyography, SD = Standard
deviation
Among baseline clinical and investigation parameters, MSS,
MBI0, and relative lymphocyte percentage showed significant
positive correlation, and duration of symptoms, AST, ALT, ESR,
platelet count, and TLC showed significant negative correlation
with MBI at 1 month and 3 months when studied in all thirty
patients [Table 4].
Muscle biopsy was done in six patients, which was normal
in two (who included patients of dengue virus infection)
and abnormal in four (dermatomyositis [1], polymyositis [1],
myopathy secondary to SLE [1], and unknown cause [1]).
Biopsy was done in those cases where the diagnosis was not
made after initial investigations or in cases who presented with
long duration symptoms.
Discussion
Patients of acute dengue infection
Out of total thirty patients, 14 were positive for either dengue
NS1 antigen and/or IgM antibody against dengue virus. Of
this, five had hypokalemia and nine had normokalemia. When
patients of dengue were compared with patients without
dengue infection; fever (P = 0.001), hyporeflexia (P = 0.02),
leukopenia (P = 0.04), relative lymphocytosis (P = 0.00),
and thrombocytopenia (P = 0.001) were significantly
more common with significantly shorter duration of
symptoms (P = 0.04), lower platelet count (P = 0.001),
lower total leukocyte count (TLC) (P = 0.01), and higher
lymphocyte percentage (P = 0.001) in patients with dengue
infection [Table 2]. On comparing patients of dengue with
hypokalemia with those of dengue without hypokalemia,
hyporeflexia (P = 0.09), serum CK <10 times (P = 0.01), and
leukopenia (P = 0.09) were more common in dengue with
hypokalemia while serum CK >10 times (P = 0.01) and
thrombocytopenia (P = 0.03) were more common in dengue
without hypokalemia. Furthermore, in patients of dengue with
hypokalemia, total serum CK level (P = 0.08) and TLC (0.07)
were lower and platelet count (0.03) was higher compared to
those without hypokalemia [Table 3].
Correlation studies
Baseline severity in the form of MSS and MBI at presentation
did not show any correlation with baseline clinical or
investigation parameters which included age, duration of
symptoms, MSS, serum CK, aspartate aminotransferase (AST),
Acute myopathy is poorly defined entity that can be caused
by various etiologies with different manifestations that need
to be approached differently compared to common chronic
myopathies. Although there are studies describing different
etiologies causing acute myopathy, prospective study analysis
of acute myopathy as a whole is lacking in literature. This is
the first study according to best of our knowledge which has
tried to look in this aspect.
Of the total thirty patients studied, two‑third of them were
males with mean age in the younger age group 29.3 ± 11.5 years,
ranging from 10 to 50 years. Although the duration of
symptoms in inclusion criteria was <4 weeks, majority of the
patients presented within 1st week of symptom onset with the
mean duration of 6.4 days. Clinical features of acute myopathy
patients in this study were similar to those of more commonly
seen chronic myopathy with symmetric proximal weakness in
all patients. One‑third patients showed distal weakness and
five patients showed neck and truncal weakness. However,
unlike chronic myopathy, fever was frequently seen in more
than half of the patients and myalgia was the second most
common associated symptom seen in one‑third of patients
studied. Furthermore, patients had muscle swelling rather
than atrophy that is commonly seen in chronic myopathy.
Hyporeflexia was also more frequent in acute myopathy (40%),
which is usually late feature in chronic myopathy when there
is marked atrophy of muscles. Hyporeflexia is commonly seen
in anterior horn cell disorder, radiculopathy, or neuropathy
with usually late finding in myopathy when loss of muscle
bulk leads to reflex loss. Such high presence of hyporeflexia
in acute cases as seen in this study indicates cause other than
just loss of muscle bulk. It is seen that acute myopathy due to
viral myositis or electrolyte imbalance can have early loss of
reflexes due to reduced excitability of the muscle fibers.[4,6,12‑15]
Annals of Indian Academy of Neurology, Volume 20, Issue 1, January-March 2017
18
Verma, et al.: Acute muscle dysfunction and dengue myopathy
Table 2: Comparison of demographic, clinical features, disability status, blood investigations, and electrophysiology
findings between patients with and without dengue infection
Variable
Age (years)
Sex
Males (n)
Female (n)
Duration of symptoms (days)
Fever
Muscle pain
Muscle swelling
Skin lesions
Weakness
Proximal only
Proximal and distal
Neck or truncal weakness
MRC sum score (0-60)
DRTs
Normal
Hyporeflexia
MBI at presentation
Good (>12)
Poor (≤12)
Total serum CK (IU/L)
<10 times ULN
>10 times ULN
AST (IU/L)
ALT (IU/L)
Serum potassium (mmol/L)
ESR (mm in 1 h)
Electrophysiology
Normal
Abnormal NCS
Abnormal EMG
Abnormal NCS or EMG
Total hemoglobin (g/dl)
PCV (%)
Platelet count (×103 cells/µl)
Thrombocytopenia (<150×103 cells/µl)
Total leukocyte count (cells/µl)
Normal (400–11,000)
Leukocytopenia (<4000)
Leukocytosis (>11,000)
Relative lymphocyte (%)
Relative lymphocytosis (>35%)
Dengue serology
NS1
IgM antibody
Both positive
Dengue (n=14)
Nondengue (n=16)
P
30.57±8.5
28.19±13.8
0.57
11 (78.6)
3 (21.4)
3.50±1.1
13 (92.9)
6 (42.9)
0
4 (28.6)
9 (56.3)
7 (43.8)
8.94±9.4
4 (25.0)
5 (31.3)
2 (12.5)
1 (6.3)
0.26
6 (42.9)
8 (57.1)
2 (14.2)
45.86±5.7
11 (68.8)
5 (31.3)
3 (18.8)
47.38±6.2
5 (35.7)
9 (64.3)
13 (81.3)
3 (18.8)
0.02
9 (64.3)
5 (35.7)
3411.98±4236.7
7 (50.0)
7 (50.0)
197.64±204.5
95.82±91.2
3.60±0.9
16.00±5.1
13 (81.3)
3 (18.8)
2936.13±5144.8
12 (75.0)
4 (25.0)
172.63±227.8
85.54±130.7
3.37±0.9
24.94±16.7
0.42
12 (85.7)
2 (14.3)
2 (14.3)
2 (14.3)
13.34±2.2
43.39±4.5
90.71±58.2
11 (78.6)
4958.57±2472.5
7 (50.0)
6 (42.9)
1 (7.1)
37.00 (6.8)
9 (64.3)
10 (62.5)
0
6 (37.5)
6 (37.5)
12.34±1.4
41.99±5.3
264.38±156.1
1 (6.3)
11,193.13±7857.0
10 (62.5)
1 (6.3)
5 (33.3)
23.25±8.5
1 (6.3)
0.00
0.00
27 (2.7–269.5)
7 (50.0)
3 (21.4)
4 (28.6)
NA
NA
NA
0.04
0.001
0.71
0.49
0.16
OR (CI)
39.0 (3.8–399)
0.27
0.73
0.50
7.8 (1.5–41.2)
0.79
0.26
0.76
0.81
0.48
0.06
0.23
0.14
0.45
0.00
0.00
0.01
0.04
55 (5–602.2)
MRC = Medical Research Council, DRTs = Deep tendon reflexes, MBI = Modified Barthel index, PCV = Packed cell volume, CK = Creatine kinase,
ULN = Upper limit of normal, AST = Aspartate aminotransferase, ALT = Alanine transaminase, ESR = Erythrocyte sedimentation rate, NCS = Nerve conduction
studies, EMG = Electromyography, CI = Confidence interval, OR = Odds ratio, NS1 = Nonstructural protein 1, NA = Not available
In investigation profile, mean serum CK level was 3158 IU/L,
ranging from 240 IU/L to 18540 IU/L. One‑third had more than
ten times rise in CK, one‑third 3–10 times, and the rest <3 times
rise. This increase in muscle enzymes suggests structural damage
rather than just functional impairment as the cause of weakness in
our study patients. Raised CK is commonly seen in viral myositis,
acute bacterial myositis, rhabdomyolysis, drug‑ and toxin‑induced
myopathy, while it is less common in pyomyositis, parasitic or
fungal myositis, electrolyte‑ and endocrine‑related myopathy,
except for severe hypokalemia and hypothyroidism.[7,8,15‑17]
Annals of Indian Academy of Neurology, Volume 20, Issue 1, January-March 2017
19
Verma, et al.: Acute muscle dysfunction and dengue myopathy
Table 3: Comparison of demographic, clinical features, disability status, blood investigations, and electrophysiology
findings between patients of dengue infection and hypokalemia and dengue infection without hypokalemia
Variable
Age (years)
Sex
Males (n)
Female (n)
Duration of symptoms (days)
Fever
Muscle pain
Muscle swelling
Skin lesions
Weakness
Proximal only
Proximal and distal
Neck or truncal weakness (%)
MRC sum score (0–60)
DRTs
Normal
Hyporeflexia
MBI at presentation
Good (>12)
Poor (≤12)
Total serum CK (IU/L)
<3 times ULN
3–10 times ULN
>10 times ULN
AST (IU/L)
ALT (IU/L)
Serum potassium (mmol/L)
ESR (mm in 1 h)
Electrophysiology
Abnormal NCS
Myopathic EMG
Myopathic EMG with spontaneous activity
Total hemoglobin (gm/dl)
PCV (%)
Platelet count (×103 cells/µl)
Thrombocytopenia (<150×103 cells/µl)
Total leukocyte count (cells/µl)
Normal (4000–11,000)
Leukocytopenia (<4000)
Leukocytosis (>11,000)
Relative lymphocyte (%)
Relative lymphocytosis (>35%)
Dengue without
hypokalemia (n=9)
Dengue with
hypokalemia (n=5)
P
28.44±7.1
34.4±10.2
0.22
8 (88.9)
1 (11.1)
3.56±1.1
9 (100)
5 (55.6)
0
4 (44.4)
3 (60.0)
2 (40.0)
3.40±1.1
4 (80)
1 (20.0)
0
0
0.51
4 (44.4)
5 (55.6)
1 (20)
47.11±5.4
2 (40.0)
3 (60.0)
1 (20)
43.60±6.3
5 (55.6)
4 (44.4)
0
5 (100.0)
0.09
7 (77.8)
2 (22.2)
4889.08±4705.23
0 (0.0)
2 (22.2)
7 (77.8)
140.33±65.2
77.6±47.7
4.1±0.5
15.22±5.0
2 (40.0)
3 (60.0)
753.2±558.6
2 (40.0)
3 (60.0)
0
300.80±326.7
128.7±142.7
2.6±0.6
17.40±5.6
0.27
0
8 (88.9)
1 (11.1)
13.9±1.9
43.94±4.0
67.00±33.7
9 (100)
2 (40.0)
4 (80.0)
1 (20.0)
12.3±2.5
42.4±5.7
133.40±72.0
2 (40.0)
5678.89±2850.1
6 (66.7)
2 (22.2)
1 (11.1)
35.56±6.4
5 (55.6)
3662.00±593.5
1 (20.0)
4 (80.0)
0
39.60±7.4
4 (80.0)
0.81
0.36
0.30
‑
0.22
1.0
‑
0.29
0.08
0.01
0.34
0.33
0.001
0.47
0.1
1.0
0.21
0.56
0.03
0.03
OR=5.5 (1.6–19.3)
0.07
0.09
0.31
0.58
MRC = Medical Research Council, DRTs = Deep tendon reflexes, MBI = Modified Barthel index, PCV = Packed cell volume, CK = Creatine kinase,
ULN = Upper limit of normal, AST = Aspartate aminotransferase, ALT = Alanine transaminase, ESR = Erythrocyte sedimentation rate, NCS = Nerve conduction
studies, EMG = Electromyography, OR = Odds ratio
Spontaneous activity in EMG was seen in eight patients.
Small amplitude, short duration polyphasic MUAP with
early recruitment in myopathy occurs as a result of drop
out of muscle fibers from the motor unit with no loss in total
number of motor unit. Spontaneous activity in the form of
fibrillation or positive sharp waves can occur in few causes
of myopathy, especially in inflammatory causes with muscle
membrane irritability. NCS is usually normal in myopathies
except for reduced CMAP that can be seen with involvement
of distal muscles. Any other abnormality in NCS suggests
involvement of structures other than muscles. Spontaneous
activity in myopathy suggests either inflammation or necrosis
of the muscle.[10] Polymyositis, dermatomyositis, and myositis
secondary to SLE are known to show spontaneous activity in
Annals of Indian Academy of Neurology, Volume 20, Issue 1, January-March 2017
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Verma, et al.: Acute muscle dysfunction and dengue myopathy
Table 4: Correlation of disability outcome parameters at
1 and 3 months with other variables in all thirty patients
Variable
Age (years)
Duration of symptoms (days)
MRC sum score
MBI0
Total serum CK (IU/L)
Serum potassium (mmol/L)
AST (IU/L)
ALT (IU/L)
ESR (mm in 1 h)
PCV (%)
Platelet count (×103 cells/µl)
Total leukocyte count (cells/µl)
Relative lymphocytosis (%)
MBI1
MBI3
r
P
r
P
0.21
−0.63
0.13
0.40
−0.18
−0.34
0
−0.10
−0.46
−0.18
−0.59
−0.50
0.58
0.26
0.001
0.50
0.03
0.35
0.07
1.00
0.61
0.01
0.37
0.00
0.01
0.00
−0.15
−0.37
0.40
0.33
−0.42
−0.24
−0.40
−0.42
−0.22
−0.15
−0.34
−0.08
0.37
0.44
0.05
0.03
0.07
0.2
0.20
0.03
0.02
0.24
0.94
0.06
0.66
0.04
MRC = Medical Research Council, CK = Creatine kinase, AST = Aspartate
aminotransferase, ALT = Alanine transaminase, ESR = Erythrocyte
sedimentation rate, PCV = Packed cell volume, MBI = Modified Barthel index
EMG. Two cases of dengue also showed spontaneous activity.
Although spontaneous activity is not a commonly feature in
muscle weakness secondary to dengue fever, some reports
suggest that it can be present in some cases.[4,13,18]
Muscle biopsy was done in six cases which revealed
polymyositis in one patient, dermatomyositis in one,
nonspecific inflammatory myopathy due to SLE in one,
nonspecific inflammatory myopathy in one, and normal in
two patients of dengue. Polymyositis and dermatomyositis
typically present with subacute symptoms of months but can
present acutely also. In a study, muscle biopsy was done in 15
SLE patients with muscle symptoms and up to 50% of them
showed myositis. Clinical evidence of myositis was present
in 8.8% of SLE patients in registry.[19] Two patients of dengue
fever who showed spontaneous activity underwent biopsy.
Both of them had normal study. Studies of muscle biopsy in
dengue myositis have revealed a range of findings from mild
lymphocytic infiltrate, lipid accumulation, mitochondrial
proliferation to foci of severe muscle damage in the form of
hemorrhages and myonecrosis.[4,13,20] Histopathology in patients
of hypokalemic paralysis due to dengue is lacking.[13]
Etiology was identified in 29 out of thirty cases. With 14 cases,
dengue was the most common cause of acute myopathy in
this study, followed by hypokalemia due to causes other
than dengue in eight patients, pyomyositis in three, and one
each of dermatomyositis, polymyositis, hyperthyroidism, and
myopathy secondary to SLE. Cause in one case could not be
identified. In patients with dengue, five had hypokalemia
and nine had normokalemia. Viral myositis and electrolyte
disturbance frequently manifest acutely as seen in earlier
studies. Frequently reported cause of viral myositis is
benign acute myositis due to influenza A or B seen more
commonly in western population. [1,21,22] Many of them
develop symptoms over hours today.[12,13,21,23‑25] However, in
recent years, neurological manifestations of dengue fever are
frequently being identified and reported.[25,26] Acute myopathy
due to dengue is one among them, which is one of the most
common causes of acute myopathy due to infection and virus
in areas where dengue is endemic. It is usually seen in rainy
season when the dengue outbreaks occurred and reduced
significantly as the mosquito breeding decrease with passing
off of rainy season. The muscle involvement in dengue fever
patients can be in the form of simple myalgia, myositis,
hypokalemic paralysis, or rhabdomyolysis. In our study of
14 cases due to dengue, nine cases were of myositis and five
due to hypokalemic paralysis. Hypokalemic weakness was
seen in 13 cases, which included five cases due to dengue
fever, three cases due to hypokalemic periodic paralysis,
and one case each of renal tubular acidosis due to Sjogren’s
syndrome, renal tubular acidosis of unknown cause, acute
pancreatitis, hyperthyroidism, and drug induced. These
causes are similar to previous studies which studied etiologies
in cases of hypokalemic paralysis.[12,14] Although the exact
mechanisms as to why dengue causes hypokalemia are largely
unknown, many postulated mechanisms are mentioned
in literature. First, the presence of endothelial dysfunction
occurring in dengue causes leakage of fluid and electrolytes
from intravascular compartment. Second, renal tubular
damage occurs in dengue fever which causes tubular loss of
potassium. Third, stress due to dengue infection causes release
of catecholamines and insulin, which leads to intracellular shift
of potassium causing hypokalemia.[27] The causes also included
two patients of hyperthyroidism, of which one patient had
hypokalemia while the other had normokalemia. Both of
them were also positive for anti‑thyroid peroxidase antibody.
The thyrotoxic periodic paralysis is one of the causes of
hypokalemic paralysis. Increased sodium‑potassium ATPase
activity by thyroid hormone leads to rapid and massive shift
of potassium intracellularly mainly muscles, hence leading to
hypokalemia and weakness. When the hypokalemia is severe,
it leads to structural muscle damage resulting in raised muscle
enzymes. Graves’ thyroid disease can also lead to muscle
weakness of proximal predominant without hypokalemia
associated with normal or hyperreflexia with normal CK level.
The reason of weakness in this is increased basal metabolic
rate, leading to depletion of energy stores resulting in easy
fatigability and weakness. The weakness in Graves’ disease is
of longer duration compared to shorter episodic nature seen in
thyroid hypokalemic periodic paralysis.[11,14] In our study, no
cases of leptospirosis were seen though it remains important
cause of myositis in certain endemic areas. Leptospirosis is
endemic in five states (Gujarat, Maharashtra, Kerala, Tamil
Nadu, Karnataka) and union territory of Andaman and
Nicobar Islands. [28] Leptospirosis though not uncommon
in Uttar Pradesh is relatively less common cause of febrile
illness as compared to southern and western states of India.
This might explain the absence of leptospirosis cases in our
study. In our study, no cases had hypokalemic paralysis due to
acute gastroenteritis. Although gastroenteritis is a well‑known
cause of hypokalemia, not much information is available about
muscle paralysis due to hypokalemia, following gastroenteritis.
In a report presented by Yurdakök et al., among 162 moderately
dehydrated children caused by acute gastroenteritis, 15 (90%)
were found to be hypokalemic (K+<3 mEq/L). None of these
patients had paralysis due to hypokalemia.[29] In another study
by Kayal et al., out of 56 patients of hypokalemic paralysis, only
two had acute gastroenteritis.[30] These studies might indicate
that though hypokalemia is common in gastroenteritis, it
is rarely severe enough to cause significant paralysis. In
Annals of Indian Academy of Neurology, Volume 20, Issue 1, January-March 2017
21
Verma, et al.: Acute muscle dysfunction and dengue myopathy
addition, majority of patients of gastroenteritis who are
critically ill are admitted in Medicine Unit of our hospital
rather than neurology unit which might explain the absence
of gastroenteritis cases in our study.
The baseline clinical severity parameters such as MSS and
MBI0 failed to show any correlation with clinical, biochemical,
hematological, or electrophysiological variables. However,
the parameters of disability status at follow‑ups such as MBI1
and MBI3 showed some notable correlations. Good outcome
at 1 month correlated significantly with shorter duration of
symptoms, better MBI0, lower serum potassium, lower ESR,
lower platelet count and lower total leukocyte count, and
higher relative lymphocyte percentage. While higher MSS at
presentation, lower serum total CK level, thrombocytopenia, and
relative lymphocyte percentage correlated with better outcome
at 3 months. Since dengue (14 cases) and hypokalemia (seven
cases other than due to dengue) constituted 70% of total
patients and all these patients presented with <1 week
duration of symptoms, the correlation study implies that these
diseases have better prognosis compared to other causes of
acute myopathy found in this study. These findings are in
accordance with previous studies which showed excellent
outcome in patients with dengue and hypokalemia with
complete and rapid improvement after treatment.[4,12‑14,24] Since
thrombocytopenia, leukopenia, and relative lymphocytosis
were commonly seen in those with dengue fever, these
variables correlated with better outcome.
Of total thirty patients included in the study, 14 were of dengue
fever. These patients were studied separately and compared
to other 16 patients without dengue. Patients with dengue
had significantly shorter mean duration of symptoms, more
patients with fever and hyporeflexia, lower mean platelet count
and total leukocyte count, higher mean relative lymphocyte
percentage, more patients with thrombocytopenia and
leukopenia, and more patients with relative lymphocytosis.
Furthermore, though not statistically significant, dengue
patients had more patients with skin lesions, more chances of
patients presenting with both proximal and distal weakness,
higher mean total CK level, lower ESR level, and higher
mean total hemoglobin level. Hence, the presence of skin
rashes, fever, and above‑said impairments in hematological
parameters, especially in hyperacute presentation (<1 week)
of myopathy, one should suspect possibility of dengue fever
more so in endemic areas. On comparing patient of dengue with
hypokalemia with those of dengue myositis, hyporeflexia and
leukopenia were more frequent in dengue with hypokalemia
while serum CK >10 times and thrombocytopenia were seen
more frequently in dengue myositis. The weakness in dengue
with hypokalemia is mainly secondary to electrolyte imbalance
and not due to structural damage hence the CK level is raised
only marginally. In addition, there can be hyporeflexia and
involvement of distal muscles with reduced CMAPs amplitude
on NCS in dengue with hypokalemia. The inflammation
and structural damage due to myositis lead to very high
level of total serum CK level in dengue myositis and usually
takes longer time (days compared to hours in dengue with
hypokalemia) for symptoms to develop and also improve.[13]
Hence, the etiological spectrum in patients of acute myopathy
can vary from metabolic, electrolyte, infectious to endocrine
and inflammatory causes with varying clinical features,
biochemical and hematological parameters, and outcome.
There is no significant difference in electrophysiology
parameters between various etiologies. EMG is more sensitive
and NCS plays a role in ruling out other causes rather than
ruling in myopathy. Biopsy may not be needed in majority of
the patients as < 30% needed biopsy, of which only five proved
to be decisive in making diagnosis (inflammatory myopathy
in two, dermatomyositis in one, polymyositis in one and
myopathy of unknown cause in one). Still diagnosis could be
reached in all but one. Hence acute myopathy differs from
chronic myopathies that one need to investigate for infections
and electrolyte more than inflammatory, endocrine and other
causes and relies less on biopsy for diagnosis. In addition,
recovery is rapid and complete in majority which may not be
the case in chronic myopathies.
Conclusion
Acute muscle dysfunction is caused by variety of causes
including infectious and non infectious etiologies. The
infectious causes differ in various parts of India in terms of
micro-organism depending upon endemic zone. Hypokalemia
associated with various disorders is commonest cause of acute
muscle dysfunction. Dengue with hypokalemia is commonly
associated with acute motor quadriparesis in North India.
Electrodiagnostic studies ,though help in differentiating
myopathy from neurogenic causes, do not determine etiological
factors for acute myopathy. Histopathological assessment
minimally helps in acute muscle dysfunction. The prognosis of
acute muscle dysfunction is good if patients are treated early
with diagnostic accuracy.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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