Accuracy of the ice test in the diagnosis of myasthenic ptosis
Background: Diagnosis of myasthenia gravis is difficult, especially when the disease is restricted to ocular muscles. It is a well-known observation that myasthenic ptosis improves with cold and based on this, the ice pack test has been used as a tool in its differential diagnosis. The aim of the study is to investigate the diagnostic value of ice pack test as a preliminary test in the differential diagnosis of myasthenia and to find out the percentage of positivity and negativity of the ice pack test.
Keywords: Ice pack test; marginal reflex distance; myasthenia gravis; ptosis
The differential diagnosis of acquired ptosis is broad, including a variety of neurological conditions such as myasthenia gravis, myopathies, Horner syndrome, and third nerve palsy. Diagnosis of myasthenia gravis is difficult especially when disease is restricted to ocular muscles. Based on the observation that myasthenic ptosis improves in the cold, ice pack test has been used as a diagnostic tool in differentiating ptosis due to myasthenia gravis from other causes. It is believed that cooling reduces cholinesterase activity, which increases the availability of acetylcholine and may promote the efficiency of acetylcholine in eliciting depolarization at the motor end plate. The objective of this study was to investigate the diagnostic value of ice pack test as a preliminary test in the differential diagnosis of myasthenia.
This was prospective, cross-sectional, observational study carried out between September 2010 and March 2012 in the Department of Neurology, Medical College Calicut, Calicut, Kerala, India. Subjects were enrolled among consecutive patients with ptosis at presentation. A cube of ice was applied to the closed lids of the seated patient. The ice pack was held in place by the patient who was advised to hold it firmly against the eyelids without excessive pressure for 2 min. Evaluation of patients with ptosis was made by recording the marginal reflex distance (MRD) with a millimeter ruler to the nearest 1 mm, immediately before and after applying the ice pack. An improvement of more than 2 mm of MRD was considered as a positive ice pack test. The influence of the frontalis muscle was eliminated by applying digital pressure on the muscle.
A diagnosis of myasthenia was made based on the following criteria.
Patients were divided into two groups: (1) Those who had ptosis and features suggestive of myasthenia; and, (2) those who had ptosis but no features of myasthenia. Patients not falling under the myasthenia group were further followed up with relevant investigations and the diagnosis of myasthenia gravis was established. Patients of both the groups were subjected to investigations such as routine blood and urine examinations, thyroid function test, antinuclear antibody, and creatine phosphokinase estimation. Relevant investigations such as computed tomography head, magnetic resonance imaging brain, and high-resolution computed tomography (HRCT) were done in appropriate patients. In the group of patients with ptosis but without myasthenia, 3 (6%) patients had myotonic dystrophy, 14 (28%) patients had diabetic third nerve palsy, 3 (6%) patients had a midbrain infarct, 2 (4%) patients had an internal carotid artery aneurysm, 10 (20%) patients had Tolosa-Hunt syndrome, 6 (12%) patients had progressive external ophthalmoplegia, 4 (8%) patients had oculopharyngeal dystrophy, 4 (8%) patients had ophthalmoplegic migraine, 2 (4%) patients had senile ptosis, and 2 (4%) patients had postinfective polyneuritis.
The patients included in the study were those with ptosis as their presenting symptom. Ptosis was defined as drooping of the upper eyelid and calculated using MRD. MRD is the distance between the center of the pupillary light reflex and the upper eyelid margin with the eye in primary gaze. A measurement of 4–5 mm was considered normal. The amount of ptosis was the difference in MRD of the two sides in unilateral cases; or, the difference from normal in bilateral cases. Grading of ptosis was done based on MRD. In mild ptosis, MRD was equal to or <2; in moderate ptosis, it was 3 mm; and in severe ptosis, it was >4 mm.
Patients with eyelid deformities and pseudoptosis were excluded. Pseudoptosis includes conditions that simulate ptosis, but lid droop is not the result of levator malfunction.
Between September 2010 and March 2012, a total of 100 patients with ptosis were included in the study. Of these, 50 patients were diagnosed as myasthenia and 50 were due to other causes of ptosis. Both groups were age matched.
In the myasthenia group, there were 24 (48%) male and 26 (52%) female patients. In the control group, there were 19 (38%) male and 31 (62%) female patients. In the myasthenia group, the distribution of patients in the various age groups 1–20, 21–40, 41–60, and 60–80 were 8, 12, 18, and 12, respectively; and, their corresponding percentages were 16, 24, 36, and 24, respectively. In the control group, the distribution of patients in the various age groups 1–20, 21–40, 41–60, and 60–80 were 7, 8, 25, and 10, respectively; and, their corresponding percentages were 14, 16, 50, and 20, respectively. There was unilateral ptosis in 12 patients in the myasthenia group and bilateral involvement in 38 patients. Among the cases with bilateral ptosis, 34 patients had unequal involvement of both eyes and 14 patients had the manifestations of fluctuating ptosis. Hence, 46 patients in the myasthenia group (unilateral ptosis in 12 and unequal involvement of both eyes in 34 patients) had unequal involvement of ptosis. In the control group, 35 patients had unilateral involvement while 15 patients had bilateral involvement. The grading of ptosis in both the groups based on their MRD is given in [Table 1]. Diurnal variation was present in 43 patients (86%) and absent in 7 (14%) patients in the myasthenia group; while, in the control group, only 2 patients had a diurnal variation.
Diplopia was present in 17 (34%) patients in the myasthenia group in addition to ptosis; while in the control group, diplopia was present in 13 (26%) patients. The frequency of other symptoms, signs, and bedside tests are given in [Table 2], [Table 3], [Table 4], respectively.
The ice pack test was positive in 48 (96%) patients and negative in 2 patients of the myasthenia group. In the control group, 6 (12%) patients had a false positive ice cold test and in the remaining 44 patients (88%), the ice pack test was negative. No complications were observed during application of the ice pack.
RNS was positive in 35 (70%) of the myasthenia patients. Of these, 25 (51.7%) patients showed a decremental response in the orbicularis oculi and nasalis muscles. In the control group, two patients had a positive RNS in the orbicularis oculi.
Neostigmine test was done in 47 patients in the myasthenia group, of whom, 39 showed a positive response and 8 showed a negative response. In the control group, neostigmine test was done in 47 patients, of whom 1 showed a false positive response while 46 patients showed a negative response.
AChR-Abs were done in 17 patients, of whom 6 patients had a positive value in the myasthenia group, while it was not done in any patient in the control group. HRCT chest was done in 37 (74%) patients in the myasthenia group and 18 (36%) patients had a thymoma. It was not done in any of the patients belonging to the control group.
Based on the Myasthenia Gravis Foundation of America (MGFA) classification, 24 (48%) patients belonged to Class I, 8 (16%) patients to Class IIa, 2 (4%) patients to Class IIb, 3 (6%) patients to Class IIIa, 3 (6%) patients to Class IIIb, 3 (6%) patients to Class IVa, 3 (6%) patients to Class IVb, and 4 (8%) patients to Class V.
In our study group, there was almost an equal incidence of female and male patients. Although myasthenia is considered as being more prevalent among female patients, there is a study in which there has been an equal incidence of male and female patients. In the control group with ptosis, there was a predominance of female over male patients. In the myasthenia group, maximum number of patients, 18 (36%), belonged to the 41–60 year age group, and in the control group also, maximum number of patients, i.e., 25 (50%) belong to the same age group, 41–60. Myasthenia is considered a disease most evident in young female and elderly male patients. In this study group, we have excluded other myasthenic patients who presented with symptoms other than ptosis, and this may be the reason for the difference in the patient number in the various age groups and also the difference in sex incidence from that found in literature. There was unilateral involvement in 12 patients (24%) with myasthenia; and, out of the 38 bilateral cases, 34 had asymmetrical involvement of one eye (89%). In the control group, 35 patients had unilateral involvement (70%), while 15 patients had bilateral involvement, with five of them having asymmetrical involvement. Hence, asymmetrical ptosis is characteristic of myasthenia.
Diurnal variations were present in 43 (86%) patients and also form a hallmark of the disease. Diplopia in addition to ptosis was present in 17 (34%) patients in the myasthenia group in our study. In the study by Leeamornsiri et al., the incidence of diplopia was 38%.
Difficulty in chewing, speaking, and swallowing was present in 24% of the myasthenic patients while it was present in 2 (4%) patients in the control group. Proximal muscle weakness was present in 18 (36%) patients. Respiratory difficulty was present in 4 (8%), bulbar weakness in 12 (24%) and proximal muscle weakness in 18 (36%) patients. In another study, the incidences of bulbar and proximal muscle weakness were 56.25% and 32.25%, respectively. Four (8%) patients were in myasthenic crisis in our study. An Indian study reported a much lower incidence (1.23%) of myasthenic crisis. Orbicularis oculi weakness was present in 44 (88%) patients of the myasthenia group.
Eye fatigability was positive in all the subjects in the myasthenia group. Arm abduction was positive in 64% of the patients. The positivity in six patients having only ocular symptoms may be due to the strenuous effort involved in arm abduction test. Heel rising test was positive in all the patients with generalized myasthenia.
Ice pack test had a sensitivity of 96% (true positive) and a specificity of 88% (true negative) with a P value of <0.05, which was significant. The positive predictive value of the test was 88%, and the negative predictive value 95%. No complications were observed in our study during the application of the ice pack. Ertas et al., reported a sensitivity of 80% and specificity of 100% in their study  while Tabassi et al., have reported a 100% sensitivity and specificity for the test in their study. RNS had a sensitivity of 70% and a specificity of 95% with a P value of <0.05, which again was significant. The positive predictive value of the test was 96% and the negative predictive value was 76%. In three other studies, the RNS positivity was reported to be 76.74, 76.52%, and 79.5, respectively.,, Neostigmine test had a sensitivity of 83% and a specificity of 97% with a P value of <0.05, which was significant. The positive predictive value of the test was 97% and the negative predictive value was 85%. In two other studies, neostigmine positivity was reported to be 100% and 90%, respectively.,
AChR-Abs were found to be positive in 6 patients out of 17 (28%) individuals with ocular myasthenia.
One study found AChR-Abs in 93, 88, and 71% of individuals with moderate to severe generalized myasthenia gravis, mild generalized myasthenia, and ocular myasthenia, respectively. Others have found binding AChR-Abs in 80–90% of those with generalized disease ,, and in 40–55% of those with ocular myasthenia. Thus, in comparison to the other tests, the ice-pack test was found to be having a high sensitivity and specificity in diagnosing myasthenic ptosis.
The ice pack test is an easy, safe, cheap, and reliable test to be used at bedside in the differential diagnosis of myasthenic ptosis. It has got a higher negative predictive value and sensitivity compared to the RNS or neostigmine test. The major disadvantage of the ice test is that it is only applicable when ptosis is present and is not helpful in patients with an isolated proximal limb weakness.
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Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4]