Year : 2007 | Volume
: 10 | Issue : 3 | Page : 191--195
An unusual cause for weakness in a girl
S Khadilkar1, Ajith Cherian2, Sanjeev V Thomas2,
1 Department of Neurology, Jaslok Hospital, Mumbai, India
2 Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India
Room No. 110, New Wing 1st Floor, Bombay Hospital and Medical Research Center, New Marine Lines, Mumbai - 400 020
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Khadilkar S, Cherian A, Thomas SV. An unusual cause for weakness in a girl.Ann Indian Acad Neurol 2007;10:191-195
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Khadilkar S, Cherian A, Thomas SV. An unusual cause for weakness in a girl. Ann Indian Acad Neurol [serial online] 2007 [cited 2020 Sep 23 ];10:191-195
Available from: http://www.annalsofian.org/text.asp?2007/10/3/191/34804
A 12-year-old girl was admitted with the complaints of a tendency to lean to the left side while walking and mild weakness of both lower limbs of two months' duration. She was born of a nonconsanguineous marriage and had had normal growth and development. She first noticed that while running she was unable to keep pace with her friends. She had no tendency for tripping or buckling of her knees. There was mild difficulty in getting up from squatting posture. There was no history of weakness of the intrinsic muscles of feet or wasting in the lower limbs. There was no weakness or wasting of upper limbs; no history of cramps, pain on muscle exertion, urinary discoloration, or of the second wind phenomenon; no bladder or bowel disturbances; no sensory complaints in the upper or lower limbs; no dysphagia, dysarthria, diplopia, ptosis, or facial weakness;no hearing difficulty; and no dysponea, palpitations, or chest pain. She was doing very well at school and was scoring an A grade. She gave no history of seizures, abnormal movements, photosensitivity, or of diurnal variation of symptoms, and she had no dysthyroid features. She had not attained menarche. Her brother and sister were normal. A male maternal cousin has mental retardation and another (paternal) male cousin has epilepsy.
On examination she was found to be alert, cheerful, and well oriented. There was mild scoliosis to the right at the level of the dorsal spine with accentuated lumbar lordosis [Figure 1]. The higher mental functions and cranial nerves were normal. The motor system showed normal tone bilaterally. There was mild wasting of the supra spinatus with winging of scapulae bilaterally.. In the upper limb, shoulder abduction and internal rotation were normal; external rotation power was grade 3 and flexion and extension were weak (grade 4+) bilaterally. The elbow, wrist, and hand-grip power were normal bilaterally. Her trunk flexors (the rectus abdominus) were weak (she had to roll over to get up), while the erector spinae were strong; Beevor's sign was negative. Lower limb bulk was normal. External rotation at the hip was considerably weak (grade 3); hip extension was grade 4-. There was asymmetric weakness of internal rotation (right 4+ and left 3). Hip flexion, abduction, and adduction were grade 4+ bilaterally. Power at the knee and ankle joints were normal. She could walk on her heels, toes, and the inner and outer border of her soles. She had a waddling gait and difficulty in getting up from a squatting position without support. There was no demonstrable fatigability or myotonia. With regard to the deep tendon reflexes: the biceps and knee jerks were absent, while supinator and triceps jerks were elicitable on reinforcement bilaterally; the ankle jerks were normal. The plantar relex was of the flexor type bilaterally and the abdominal reflexes were normal. No sensory or cerebellar signs were present.
Hemoglobin 15.0 gm/100 ml, PCV 48%, total leukocyte count 7,800 cells/mm 3 (polymorphs 61%, lymphocytes 36%, and eosinophils 03%). ESR (Westergen) 7 mm/h, prothrombin time 12/12 (INR = 1.00] s, serum urea nitrogen 5 mg%, serum potassium 4.60 mEq/l, serum sodium 140 mEq/l, creatinine 0.50 mg/dl, fasting glucose 80 mg/dl, cholesterol 235 mg/dl, HDL cholesterol 34 mg/dl, triglycerides (TG) 228 mg/dl, SGOT 22 U/l, SGPT 25 U/l, alkaline phosphatase 762 U/l bilirubin total 0.40 mg/dl, bilirubin direct 0.10 mg%, total proteins 6.70 g/dl, albumin 4.00 g/dl, globulin 2.70 g/dl, lactate dehydrogenase (LDH) 175 U/l, creatine phosphokinase (CPK) 79 U/l, inorganic phosphorus 4.30 mg/dl. Thyroid function tests were normal, serum lactate 1.9 mol/l (normal 0.7-2.5 mol/l) ECG and echocardiography were normal; ultrasonogram of abdomen was normal.
Nerve conduction studies showed normal latencies and compound muscle action potential characteristics for the upper and lower limbs. Repetitive nerve stimulation done at 3 Hz was negative (preexercise and postexercise-immediate, 1 min, 2 min, 3 min, and 5 min). Needle (concentric) EMG showed no evidence of active or chronic denervation. Motor unit potentials from the rectus femoris and tibialis anterior had low amplitudes, in the range of 300 Ávolts, and a duration of 4-5 milliseconds. Recruitment was early and full. Muscle biopsy (rectus femoris) showed that the muscle fibers were normal in morphology, with no features of myopathy or denervation. Endomysial collagen was normal; no diagnostic pathology; normal dystrophin and sarcoglycan immunolabeling seen [Figure 2]a and b.
A diagnostic test was performed
In this 12-year-old girl, the history and clinical examination demonstrate weakness of the proximal musculature of a symmetrical nature and of brief duration. The hip girdle, shoulder girdle, and trunk muscles are weak. While there is no pattern to the weakness of the lower limb musculature, the weakness of the shoulder girdle is more pronounced in the scapular muscles and the spinatii. The semi-distal and distal muscles are normal, sensations are preserved, and the deep tendon reflexes are reduced in a patchy manner. In addition to the findings in the motor system, she also had mild scoliosis. Based on these findings, there are two possible anatomical levels that may have been involved by the disease process: the muscles and the anterior horn cells. The involvement of the proximal musculature and the symmetrical nature is more in keeping with a myopathy, whereas the changes in the reflexes point to a disease of the anterior horn cells. The common belief is that the deep tendon reflexes tend to be affected more often, and earlier, in diseases of the anterior horn cells as compared to muscle diseases. However, it is important to remember that the deep tendon reflexes can be affected early in the myopathies as well. For example, in the commonly seen Duchenne muscular dystrophy, patients lose upper limb reflexes early; these reflexes are regularly absent at a stage when the upper limb is not yet much weakened. This is believed to be a reflection of the affection of the intrafusal muscle fibers. In the following text, we will consider various groups of myopathies.
In the present case, given the brief duration of the symptoms, the proximal nature of the process, and its nonfamilial nature, inflammatory myopathies come first to mind. However, there are many unusual points about this diagnostic group. In childhood, dermatomyositis is much more common than polymyositis, but there is no mention of skin rashes or of other systemic symptoms. A significant proportion of patients with inflammatory myopathies have dysphagia, a strong pointer to the diagnosis, which is not present in this patient. In the clinical profile, there is mention of preferential weakness of the scapular muscles, which is unusual for the inflammatory myopathies. With these clinical points, a diagnosis of one of the inflammatory myopathies appears less likely. The normalcy of the serum CPK, the lack of positive activity on the EMG, and the normal histology makes the diagnosis very unlikely. It should be noted that any one of these parameters [CPK, EMG studies, or muscle biopsy] could well be within normal limits in a case of inflammatory myopathy, but all three being normal would most probably exclude this diagnosis.
The second group of conditions to be considered are the muscular dystrophies. There are various dystrophies that can present in a 12-year-old female. The duration of symptoms of 2 months, is too brief for to support a diagnosis of one of the dystrophies, but time and again, it has been noticed that patients come to know about the disability only when it reaches a certain magnitude and begins to affect the performance of daily chores. The phenotypes of the dystrophies are variable and there is a huge overlap between the genotypes and the phenotypes; hence phenotype has limited utility for diagnosis. However, winging of scapulae is associated with certain dystrophies, of which fascioscapulohumeral dystrophy (FSHD) comes immediately to mind. This patient [Figure 1] does show a mild degree of scapular winging, but it seems much less pronounced than what is seen in FSHD. Also, the scapulae do not seem to ride and to produce the typical hump. In FSHD, the weakness of muscles is such that the scapulae move upwards and form protuberances in the shoulder region that can be seen from the front of the patient. Even though many other conditions lead to winging of scapulae, such a configuration is seen most often with FSHD. This is not the case in the present patient. Further, FSHD is an autosomal dominant disease; it affects the facial musculature and tends to be asymmetrical. In this patient, the absence of a family history would argue against an autosomal dominant condition, although sporadic forms are well known. Calpainopathy is also known to produce pronounced weakness of the scapular muscles but, in addition, patients also have selective weakness of the adductor muscles of the hip. Lastly, it needs to be pointed out that, particularly in toddlers and some adolescents, it can be difficult to be certain about the weakness of the scapular muscles.
Other limb-girdle muscular dystrophies (LGMD) need a brief mention, but many have selective muscle involvement that is not seen in this patient. For example, dysferlinopathy would have distal muscle involvement, particularly of the gastrocnemius muscle. But, in the LGMDs, the genotype-phenotype correlation is most complex and it is very difficult to guess at the molecular and structural defects, based on the clinical presentation. The normal CPK and normal histology in this case would make the whole group of dystrophies unlikely. A point of note is that histology could be only very mildly abnormal in a LGMD patient with a frank clinical weakness, as the process tends to be patchy in some patients. Immunocytochemistry is more likely to be uniformly abnormal as compared to histology. In the present case, dystrophin and sarcoglycan labeling were normal, excluding those forms of LGMDs. Dystrophinopathies would, in any case, be less likely (though not impossible) in female patients. Just to recapitulate, female patients can manifest dystrophinopathy in situations of mosaicism, an XO phenotype, and an X-autosomal translocation. It is of historical interest that the initial localization of the Xp 21 in Duchenne muscular dystrophy came from the chance study of a female patient with severe muscular dystrophy who had an X-autosomal translocation. The group of metabolic myopathies can uncommonly present with a progressive proximal muscle weakness, without prominent exercise intolerance. They tend to have a nonselective proximal muscle weakness, often with mild bulkiness of the muscles. Such patients can have a normal CPK, mildly abnormal electromyography (as seen in this patient), and the routine histology may look unimpressive; the vacuoles may be elusive. Hence, we will need information on the stains for glycogen and lipids to further evaluate the possibility of one of the metabolic myopathies. The resting lactate has been mentioned as being normal, but an ischemic forearm test with lactate measurement will be informative. The ischemic forearm test is a well-studied test and is not difficult to perform. The test shows characteristic abnormalities in the metabolic myopathies and in mitochondrial disorders. Its sensitivity is higher than that of resting lactate levels. Abnormalities of calcium metabolism result in painful myopathies, principally involving the hip girdle. In this patient, there is a mildly elevated alkaline phosphatase level and a normal phosphorus level, and it would be advisable to confirm that the calcium and vitamin D3 levels are normal.
Mitochondrial myopathies form a differential diagnosis. The nonselective proximal weakness can be a result of mitochondriopathy. The history of a maternal cousin having mental subnormality may support this diagnosis. Resting lactates are not elevated, but further evaluation with the ischemic forearm test, the Gomori trichrome stain, and electron microscopy may help in clarifying the picture. However, involvement of more than one organ system is often the main feature of mitochondriopaties, which is not seen in the present case.
Myasthenic syndromes and myotonias need a brief mention in this patient who has a pure motor limb-girdle syndrome; electrophysiology excludes these diagnoses.
Lastly, we need to consider the congenital myopathies. As a group, they present early in life and often lead to a nonprogressive muscular weakness with mild disability. Some of these conditions are known to progress slowly. In the present case, the presence of scoliosis is intriguing; it may mean that the muscular weakness is of much longer duration than what the patient has noticed and that it focused on the axial musculature. Among the congenital myopathies, the central core disease patients are known to have scoliosis. In the classical form, the scoliosis can be severe and lead to respiratory insufficiency. Such patients tend to be of very thin habitus, which is not true in the present case. To explore the possibility of congenital myopathies further, we will need the information from oxidative stains and electron microscopy.
At this stage, let us further examine the myopathology. In particular we shall need to review the information from various stains and electron microscopy to study the situation further.
Further Laboratory Reports
Calcium 11.20 mg/dl, 24h urinary calcium 528 mg/day, USG thyroid /parathyroid gland showed small isoechoeic lesion in the posterior aspect of the right lobe of the thyroid (ectopic parathyroid adenoma), serum parathyroid hormone (PTH) 600 pg/ml (and 1286 pg/ml on a second occasion). A 99 Tc radiolabeled parathyroid gland scan showed possible evidence of a PTH adenoma over the right side [Figure 2]b. X-ray of the skull and hands showed absorption of lamina dura and evidence of demineralization.
She underwent parathyroidectomy with right hemithyroidectomy under general anesthesia. The operative findings were a 3-cm swelling behind, and adherent to, the right superior pole of the thyroid gland and the surrounding structures. The inferior parathyroid appeared normal. The right recurrent laryngeal was nonrecurrent. The postoperative PTH was 61.48 pg/ml. Otherwise postoperative period was uneventful. Pathological examination of the specimen showed a tumor with different-sized lobules separated by thick fibrous septae. The adjoining, compressed, parathyroid tissue was normal. The tumor, predominantly composed of clear cells with a mixture of chief and oxyphil cells, was seen to be traversed by capillary channels. However, no capsular or vascular invasion was noted. The thyroid tissue that was removed at surgery was of normal morphology. Immunohistochemical examination was positive for Ki67- (  Patients have symmetrical muscle weakness and atrophy. Bulbar muscles and sphincters are usually spared.  Half of the patients have muscle cramps.  Some of the neuromuscular manifestations of hyperparathyroidism resemble those seen in motor neuron disease. Patient with increased PTH may present with muscle atrophy and weakness, with hyperreflexia and spasticity. Affected patients tend not to do well and disease progression is much like that seen in patients with MND. ,,
Elevated serum alkaline phosphatase and calcium levels, with depressed serum phosphate levels, are the most useful markers for primary hyperparathyroidism. Hypercalciuria is common. PTH may be elevated or normal. Osteopenia on bone radiographs suggests the diagnosis. Serum levels of CK and aldolase are usually normal, as was seen in this patient. 
These muscle disorders result from elevation in PTH in primary and secondary hyper PTH and impaired vitamin D activity in secondary hyperparathyroidism and osteomalacia. The effects on skeletal muscle are through alterations in serum Ca ++ and through direct effects on muscle metabolism. PTH stimulates protein degradation in skeletal muscle.
Electrophysiology: In primary hyperparathyroidism, the EMG study may be nearly normal or may show a high percentage of small, polyphasic motor unit potentials, compatible with a diagnosis of myopathy.  Needle EMG shows decreased motor unit potential size and increased frequency of polyphasic potentials without spontaneous activity. 
Muscle biopsy: In primary hyperparathyroidism, muscle histology generally shows no abnormalities but type 2 fiber grouping with internal nuclei and small group atrophy may be observed.  Ultrastructural studies show nonspecific changes with Z-line degeneration and vacuolization. 
In primary hyperparathyroidism, parathyroidectomy corrects the symptoms and improves strength. At times, the rapidity of recovery is striking. In the two patients seen by me, presenting with the neuromuscular manifestations of primary hyperparathyroidism, the symptoms started reversing towards end of the second week and continued to abate nearly completely over ensuing few weeks.
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