ELEVATION OF CREATINE KINASE IN AMYOTROPHIC LATERAL SCLEROSIS

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1 20 1 ELEVATION OF CREATINE KINASE IN AMYOTROPHIC LATERAL SCLEROSIS Po ten tial Confusion with Pol y m y osi ti s THOMAS M. HARRINGTON, MARC D. COHEN, JOHN D. BARTLESON, and WILLIAM W. GINSBURG Serum creatine kinase (CK) levels were recorded in 100 patients with amyotrophic lateral sclerosis (ALS). CK concentrations were elevated in 43% of the patients, with a mean level of 240 U/liter and a range of 59-1,327 Ufliter (male normal <95 Uhiter, female normal <59 Uhiter). All patients with elevated CK had muscle weakness. Seven patients were initially misdiagnosed as having polymyositis and given high dose corticosteroids without clinical benefit, prior to the diagnosis of ALS. Such diagnostic confusion can be avoided by an awareness that CK levels cannot be used to reliably differentiate between ALS and primary muscle disease such as polymyositis. In 1874 Charcot first used the term amyotrophic lateral sclerosis (ALS) to describe the motor neuron disease characterized by progressive, usually asymmetric muscle weakness and atrophy, fasciculations, and evidence of corticobulbar and pyramidal tract involvement including hyperreflexia, positive palmomental responses, and the Babinski sign (1). Weakness involves most skeletal muscle including somatic appendicular and cranial nerve groups excluding cardiac muscle and generally the extraocular muscles. Sensory, extrapyramidal, intellectual, and sphincter functions are unaffected. The diagnosis of ALS is usually From the Divisions of Rheumatology and Neurology, Mayo Clinic, Rochester, Minnesota. Thomas M. Hamngton, MD: Fellow in Rheumatology; Marc D. Cohen, MD: Fellow in Rheumatology; John D. Bartleson, MD: Assistant Professor of Neurology; William W. Ginsburg, MD: Assistant Professor of Medicine. Address reprint requests to William W. Ginsburg, MD, Mayo Clinic, Rochester, MN Submitted for publication May 18, 1982; accepted in revised form September 30, made on the basis of the patient s history and clinical examination. Patients, however, can frequently present with skeletal muscle weakness as their most prominent symptom. Additional special testing may be necessary to exclude more treatable conditions. The presence of an elevated serum creatine kinase (CK) enzyme level has been used to differentiate primary muscle disorders from neurogenic weakness. CK values are significantly elevated in polymyositis and the muscular dystrophies. Over the past decade there have been scattered reports demonstrating that CK elevations may be seen in ALS and related motor neuron diseases (2-8). Thus, CK elevations are not restricted to primary myopathic disorders. Potential confusion may therefore arise when ALS patients present with symmetric skeletal muscle weakness and are found to have elevated CK levels. The present study reviews our experience with elevated CK values in ALS, emphasizing the possible erroneous diagnosis of polymyositis. PATIENTS AND METHODS Records of 294 patients with ALS seen at the Mayo Clinic were reviewed. One hundred of these patients had CK determinations made during their evaluation. In all cases the clinical history, physical findings, and electromyogram results were consistent with a diagnosis of ALS. All patients were seen by a neurology consultant. In any case where the diagnosis was uncertain after the initial evaluation, appropriate followup was undertaken to confirm the diagnosis of ALS. RESULTS Forty-three patients had elevated CK levels and 57 patients had normal values. The male to female Arthritis and Rheumatism, Vol. 26, No. 2 (February 1983)

2 202 HARRINGTON ET AL ratio in those patients with elevated CK levels was I.5 : 1; the ratio of male to female patients with normal enzymes was 1 : 1. The mean age of onset of disease of the 100 patients studied was 57 years, with a range of The mean age of onset of symptoms of patients with ALS and elevated CK levels was 55 years compared with a mean age of 59 years in the patients with normal CK levels. The mean CK of the 43 patients with elevated values was 240 U/liter, with a range of 59-1,327 U/liter. In our laboratory, the normal CK value for men is <95 UAiter and for women, <59 UAiter. In those patients with elevated CK levels the mean value for men was 300 U/liter and for women, 138 U/liter. The mean level in the 57 patients with normal CK levels was 49 U/liter (men 58 U/liter and women 41 U/liter). The majority of patients with elevated CK had levels in the U/liter range (31 patients). Five patients had elevation of CK between U/liter and 7 had elevations over 400 U/liter (Figure 1). The mean duration of symptoms prior to CK determination was 19 months in the group with elevated CK levels (range 2 months to 6 years). Duration of symptoms in those patients with normal CK levels was 19 months (2 months to 4 years). Serum glutamic oxaloacetic transaminase (SGOT) levels were mildly elevated in most of the patients with elevated CK levels. The mean SGOT level was 27 U/liter in the group of patients with elevated CK levels, compared with 17 U/liter in patients with normal serum CK (normal SGOT <22 Uhiter). The erythrocyte sedimentation rate (ESR) was normal in 26 of 29 patients in whom the test was performed. When the ESR was elevated, it did not correlate with either disease severity or degree of CK elevation. Muscle biopsies were performed in 6 patients who had elevated CK determinations. Four of the 6 biopsies showed changes of denervation atrophy without myopathic changes. The other 2 biopsies demonstrated both denervation atrophy and associated myopathic changes consisting of enlargement of muscle fibers, centralization of sarcolemmic nuclei, and vacuolar changes in the muscle fibers. Six of the patients with elevated CK levels had been initially diagnosed elsewhere as having polymyositis and subsequently treated with high dose corticosteroids. One additional patient with proximal muscle weakness was given a of 18 r d Normal d < 95 U/L 9 < 59 U/L CK level U/L Figure 1. Creatine kinase elevations in amyotrophic lateral sclerosis. presumptive diagnosis of polymyositis despite having a normal CK value. All 7 patients with a preliminary diagnosis of polymyositis continued to worsen in condition despite corticosteroid treatment. Among the 6 patients with an elevated CK level treated with corticosteroids, the CK level dropped in 2 patients while on the treatment regimen, but there was no clinical improvement. Forty of the 43 patients (93%) with elevated CK levels had spinal somatic muscle weakness as their major presenting symptom and all 43 patients had weakness at the time of evaluation. Of the 57 patients with normal CK values, 33 (58%) had spinal somatic muscle weakness as their major presenting symptom and 48 (84%) had limb muscle weakness at the time of their evaluation. Proximal and distal limb muscles were involved with equal frequency. Sixty percent of patients with ALS and spinal somatic muscle weakness had these symptoms asymmetrically. Three of the 43 patients (7%) with elevated CK levels had corticobulbar symptoms as their major presenting complaint, compared with 24 of 57 patients (42%) with normal CK values. Fourteen of the 43 patients (33%) with elevated CK levels eventually developed corticobulbar symptoms during their evaluation, compared with 36 of 57 patients (63%) in the group with normal CK levels. Muscle cramps were noted in 65% of patients with elevated CK levels and 51% of patients with normal enzyme values. Other associated physical findings are shown in Figure 2. It should be noted that 3 patients with elevated CK levels had a history of strenuous exercise immediately prior to CK determinations. Their CK levels were 582, 527, and 685 UAiter. d

3 CK ELEVATION IN ALS 203 Muscle weakness Fasciculations Muscle atrophy Positive Babinski Increased DTR Bulbar symptoms Spasticity Foot drop Percent Figure 2. Physical findings in amyotrophic lateral sclerosis: elevated versus normal creatine kinase level. DISCUSSION Of the 100 patients with ALS in whom serum CK determinations were made, 43% were noted to have elevated values. Previous series have found percentages ranging from 35% to 100% (2-5,7). The 27 men and 16 women had mean serum CK levels of 300 U/liter and 136 Uhiter respectively. CK level did not correlate with the duration of symptoms. The 43 patients with elevated CK levels and the 57 patients with normal CK values both had a mean duration of symptoms of 19 months. The rate of progression of ALS also did not correlate with the degree of elevation of CK in our patients. In fact, one patient had his disease for 10 years with CK values greater than 600 UAiter. Elevated CK levels did correlate with spinal somatic muscle weakness. Ninety-three percent of patients with elevated CK levels noted spinal somatic muscle weakness as their major presenting symptom and 100% had such weakness at the time of their evaluation. Among the patients with normal CK levels, 58% had spinal somatic muscle weakness as their predominant presenting symptom and 84% had weakness at some time during the course of their illness. The remaining patients in each group noted corticobulbar symptoms as their major presenting complaint. Thus 7% of the patients with elevated CK and 42% of the patients with normal CK levels presented with corticobulbar symptoms. Patients with ALS and elevated CK levels had more spinal somatic muscle weakness and less cranial nerve involvement than patients with normal CK values. This finding also correlated with the extent of muscle atrophy. Seventy-seven percent (33 of 43 patients) with elevated CK levels had muscle atrophy compared with 35% (20 of 57) patients with riormal CK determinations. These results are in agreement with those of Welch and Goldberg (5) who correlated abnormal CK levels with the extent of involved muscle mass. This finding is also supported by the distribution of spinal somatic involvement. Ninety-one percent (39 of 43 patients) with elevated CK levels had involvement of both upper and lower limbs while only 58% (33 of 57 patients) with normal CK values had similar involvement. The mechanism of CK elevation in ALS is unknown. Achan and Anderson have suggested that serum CK elevation in ALS is due to leakage of the enzyme across cellular membranes in damaged or denervated muscle tissue (4). In animal studies muscle undergoing neurogenic atrophy was found to be more permeable to CK than normal or dystrophic muscle (9). Elevated CK levels might then feflect the rate of the atrophic process and the extent of the involved muscle mass at the time of measurement (5). A state of disturbed muscle metabolism has also been postulated, with increased endogenous adenosinetriphosphatase activity in mitochondria resulting in increased CK activity (10,ll). Welch and Goldberg (5) were able to

4 204 HARRINGTON ET AL correlate elevated CK levels with the extent of muscle mass undergoing denervation and atrophy. They speculated that the mechanism might be increased permeability of the muscle cell membranes or disturbed muscle metabolism, either of which could be caused by denervation or reinnervation (5). Another theory to explain the elevated CK in patients with ALS resulted from the observation that levels of CK correspond to the degree of myopathic changes on muscle biopsy (12). In one study (12), 75 of I1 1 (67%) ALS patients undergoing muscle biopsy had myopathic abnormalities such as rounding and enlargement of fibers and central migration of subsarcolemmic nuclei, in association with otherwise characteristic changes of denervation atrophy. An additional 25% of the patients had denervation atrophy alone and 7% had normal results of muscle biopsy. Although the mean CK level was more elevated in the group of patients with both denervation atrophy and associated myopathic changes on muscle biopsy, the groups with denervation atrophy alone and normal biopsy results also had elevated CK levels. Only 2 of our 6 patients who underwent muscle biopsy had both denervation and myopathic changes, and their CK levels were no higher than those of the patients showing denervation atrophy alone. Another contributing factor to elevated CK in patients with ALS might be the effect of exercise. Patients with ALS may have their CK elevated times normal by exercise, and this elevation is thought to be secondary to efflux from remaining normal muscle tissue (13,14). In only 3 of our 43 patients could the elevated CK level possibly be linked to strenuous exercise. Clearly, many patients with ALS are found to have elevated CK levels in the resting state (2-8). While the precise mechanism of elevated CK levels in patients with ALS remains uncertain, the abnormality seems related to the basic disease process of denervation and compensatory reinnervation with occasional muscle fiber hypertrophy. The clinical picture in ALS is usually distinctive. In most cases positive diagnosis can be made based on the slow progression of asymmetric muscle weakness and atrophy, coupled with upper motor neuron signs affecting muscles supplied by the cranial nerves, spinal somatic nerves, or both. The presence of fasciculations and the absence of sensory loss and pain are additional features typical of ALS. However, some patients with ALS present with roughly symmetric involvement favoring proximal muscles and limited corticobulbar symptoms, showing few upper motor neuron signs or fasciculations. Thus, diagnostic confu- sion with polymyositis can and does occur. Such had been the case in 7 of our patients, representing 7% of the patients in whom CK level was determined. The presence of an elevated CK level increases the potential for confusion between ALS and polymyositis. Helpful digerential points include the symmetry of weakness in polymyositis and the predilection for proximal limb muscle and no corticobulbar involvement in this disease. Muscle atrophy is not as common in polymyositis but occurs frequently in ALS (53% of patients in our series) (15). Muscle fasciculations, present in 90% of our ALS patients, are virtually never seen in polymyositis. Hyperreflexia, noted in 27% of our patients, is frequent in ALS and rare in polymyositis. Electromyography (EMG) is the most useful diagnostic aid. In patients with ALS, the EMG shows fasciculations, fibrillation potentials, and reduced numbers of motor unit action potentials, many of which show increased amplitude and prolonged duration (16). Despite these abnormalities, motor and sensory nerve conduction velocities are usually within the normal range in patients with ALS. These findings contrast with those in polymyositis in which the EMG reveals brief duration, small amplitude, and polyphasic motor unit potentials (17). Fibrillation potentials may also be seen in polymyositis. When doubt remains after EMG is performed, muscle biopsy may be necessary and should prove decisive. Creatine kinase levels cannot be used to reliably differentiate between neurogenic and primary myopathic diseases. Recognition of the possibility of increased CK in ALS may help to avoid confusion With polymyositis. REFERENCES 1. Charcot JM: De la sclerose laterale amyotrophique. Prog Med Virol , Williams ER, Bruford A: Creatine phosphokinase in motor neuron disease. Clin Chim Acta 27:53-56, Panitch HS, Franklin GM: Elevation of serum creatine phosphokinase in amyotrophic lateral sclerosis. Neurology , Achari AN, Anderson MS: Serum creatine phosphokinase in amyotrophic lateral sclerosis. Neurology 24: , Welch YMA, Goldberg DM: Serum creatine phosphokinase in motor neuron disease. Neurology , Munsat TL, Baloh R, Pearson CM, Fowler W: Serum enzyme alterations in muscular disorders. JAMA 226: , 1973

5 CK ELEVATION IN ALS Edmonds PJ, Ziegler DK: Diagnostic value of serum creatine phosphokinase in motor neuron disease. South Med J 68: , Koufen H, Consbruch U: Die Serum CPK activitat bei amyotropher lateral Sklerose (ALS) und anderen neurogenen musculatrophien unter Berucksichtigung differential Diagnosticher aspekte. Nervenarzt , Dawson DM: Leakage of enzymes from denervated and dystrophic chicken muscle. Arch Neurol 14: , Ionasescu V, Luca N, Vuia 0: Disturbance of oxidative phosphorylation in human dystrophic and denervated muscle, Muscle Diseases: Proceedings of an International Congress. Edifed by JN Walton, N Canal, G Scarlato. Amsterdam, Excerpta Medica Foundation, 1970, pp Ernster L, Ikkos D, Luft R: Enzymic activities of human skeletal muscle mitochondria: a tool in clinical metabolic research. Nature (London) 184: , Achari AN, Anderson MS: Myopathic changes in amyotrophic lateral sclerosis. Neurology 24: , Welch KMA, Goldberg DM: Response of serum enzymes and other biochemical constituents to strenuous exercise in control subjects and patients with motor neuron disease. J Neurol Sci 19: , Delisa JA, Tipton NM: Exercise effect on creatine phosphokinase elevation in motor neuron disease. Arch Phys Med Rehabil60: , Noms FN: Adult spinal motor neuron disease, Handbook of Clinical Neurology. Vol. 22. System Disorders and Atrophies, Part 11. Edited by PJ Vinken, GW Bruyn. Amsterdam, Elsevier North Holland, 1975, pp Warrnolts JR: Electrodiagnosis in neuromuscular disorders. Ann Intern Med 95: , Bohan A, Peter JB, Bowman RL, Pearson CM: A computer assisted analysis of 153 patients with polymyositis and derrnatomyositis. Medicine 56: , 1977