Atrophy of Foot Muscles a Measure of Diabetic Neuropathy

Pathophysiology/Complications ORIGINAL ARTICLE

Atrophy of Foot Muscles A measure of diabetic neuropathy

1 HENNING ANDERSEN, MD, PHD athy that is easily detected in the feet and 1 MICHAELA D. GJERSTAD, MD is closely related to the severity of neurop- 1 JOHANNES JAKOBSEN, MD, PHD athy. In the present study, foot muscle volume was studied in a group of long- term diabetic patients with and without neuropathy and in a group of nondiabetic control subjects. OBJECTIVE — Diabetic neuropathy is a length-dependent process that leads to reduced muscle strength and atrophy of leg muscles in some patients. We hypothesized that intrinsic foot muscles are atrophied in diabetic neuropathy and that the degree of atrophy is a measure of RESEARCH DESIGN AND motor dysfunction closely related to the neuropathic process. METHODS — Twenty-three type 1 RESEARCH DESIGN AND METHODS — Consecutive cross-sectional magnetic reso- diabetic patients (16 men and 7 women) nance images of the nondominant foot were obtained for stereological determination of the total aged 46 years (median, range 27–62) volume of the intrinsic foot muscles (VFM) in 23 long-term diabetic patients with (n ϭ 15) and with a median diabetes duration of 29 without (n ϭ 8) chronic neuropathy and in 23 matched healthy nondiabetic control subjects. years (range 16–38) were included. The Based on clinical examination, nerve conduction studies, and quantitative sensory examination, mean body weight and body height were a neuropathy rank-sum score was calculated for each patient. 73 kg (range 53–92) and 176 cm (range 155–186), respectively. Diabetic patients 3 RESULTS — Total VFM was 86 Ϯ 52, 165 Ϯ 34, and 168 Ϯ 42 cm in neuropathic patients, without and with various degrees of neu- Ͻ nonneuropathic patients, and healthy control subjects, respectively (P 0.001). There was a ropathy were selected without paying at- close inverse relationship between the neuropathy rank-sum score and the VFM (r ϭϪ0.75, P Ͻ Ϫ tention to symptoms and signs of motor 1 ϫ 10 5). disturbances. Patients with severe cardiac CONCLUSIONS — Total volume of the foot muscles is halved in patients with diabetic or lung disease, acute or chronic muscu- neuropathy. Atrophy of foot muscles is closely related to the severity of neuropathy and reflects loskeletal disorders, acute metabolic dys- motor dysfunction. regulation, other neurological or endocrine disorders, or any previous or Diabetes Care 27:2392–2385, 2004 present lower-limb asymmetric proximal weakness were excluded. None of the patients had a history of foot ulcer or symp- oss of ankle jerks and of sensation in related to muscle atrophy, whereas non- toms or signs of arterial insufficiency in the feet are early clinical signs of neuropathic patients have normal muscle the lower extremities. All case records L chronic polyneuropathy in diabetes. strength and striated muscle mass (3). In were searched for other explanations of In contrast, motor weakness with loss of the more distally situated intrinsic foot polyneuropathy, and all patients were ex- the ability to stand on the heels occurs late muscles, Brash et al. (4) observed atrophy amined by a trained neurologist who de- in the clinical course and only in a minor- in neuropathic diabetic patients using a cided whether the findings were typical of ity of diabetic patients. Previous studies specific magnetic resonance imaging diabetic neuropathy. None of the patients on motor function in diabetic neuropathy (MRI) contrast sequence; however, the at- had any significant toe or foot deformity. have relied on simple clinical tests such as rophy was not quantified. Since diabetic Twenty-three healthy control subjects the ability to stand on heels (1) and neu- polyneuropathy shows a centripetal pat- were included and matched for sex. They rophysiological examinations of motor tern of progression, quantification of the had a median age of 46 years (range 27– nerves (2). In a series of experiments in more distally situated foot muscles could 61), body height of 179 cm (range 160– long-term diabetic patients, we have ob- possibly serve as an early marker for mo- 185), and body weight of 69 kg (range served that muscle weakness in the lower- tor dysfunction in diabetic neuropathy. 55–97). All patients and control subjects leg muscles occurs to a substantial degree We hypothesized that muscular atro- gave informed consent to the study, in chronic neuropathic patients, closely phy is an integral part of diabetic neurop- which was approved by the local ethics ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● committee. The nondominant foot of all patients From the 1Department of Neurology, Aarhus University Hospital, Aarhus, Denmark; and the 2Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital, Aarhus, Denmark. and control subjects was visualized by Address correspondence and reprint requests to Henning Andersen, Department of Neurology, Aarhus MRI using a 1.0 Tesla scanner (Sigma University Hospital, 8000 Aarhus C, Denmark. E-mail: [email protected]. GE). All MRI scans were obtained with a Received for publication 14 April 2004 and accepted in revised form 15 July 2004. conventional T1-weighted Spin-Echo se- Abbreviations: MRI, magnetic resonance imaging; VFM, volume of the intrinsic foot muscles. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion quence (echo time 20 ms, repetition time factors for many substances. 540 ms) using 4-mm cross-sectional mag- © 2004 by the American Diabetes Association. netic resonance images and an intersec-

2382 DIABETES CARE, VOLUME 27, NUMBER 10, OCTOBER 2004 Andersen, Gjerstad, and Jakobsen

Figure 1—Total volume of all foot muscles in 15 type 1 diabetic patients with neuropathy, in 8 nonneuropathic type 1 diabetic patients, and in 23 nondiabetic healthy control subjects (A). Values are means Ϯ SD. Below is a cross-sectional magnetic resonance image at the metatarsal level of the foot in a neuropathic patient (B), in a nonneuropathic patient (C), and in a nondiabetic control subject (D) showing that the neuropathic diabetic patient has a substantial reduction of muscle tissues. *P Ͻ 0.001, neuropathic patients compared with nonneuropathic patients and nondiabetic control subjects. tion interval of 10 mm. A 256 ϫ 256 by a single observer using a stereological mined for the dominant median and matrix and two excitations were used. point-counting method as described pre- nondominant peroneal nerve using an The magnetic resonance images were viously (3,5). The total volume of striated electromyograph (Dantec Counterpoint) converted to digital pictures for analysis muscle (in cubic centimeters) was calcu- and standard methods. Vibratory percep- on a PC (Chameleon; Olympus). The lated by multiplying the distance between tion thresholds were evaluated at the identity of the magnetic resonance images the sections by the total cross-sectional dominant index finger pulp and at the was blinded to the observers. Within the area, the first section being randomly nondominant dorsum of the great toe us- muscle compartments, an upper level of placed within the first interslice 10-mm ing forced-choice techniques (Case IV; signal intensity for muscle tissues was de- interval. For further analysis, the volume WR Medical Electronics). A neuropathy fined. Signal intensities above this level for each patient was expressed as a per- rank-sum score was calculated for each were comparable with signal intensities of centage of the value of the individually patient based on the findings of the neu- fat tissues, allowing a separation of mus- matched control subject. ropathy symptom score, neurological im- cle tissues from “nonmuscle tissues” All patients were evaluated clinically pairment score, vibratory perception within the muscle compartments. Muscle according to a neuropathy symptom threshold test, and motor nerve conduc- fascia, tendons, and blood vessels were score (6) and a neurological impairment tion velocity, a high score reflecting severe excluded. At each image, the cross- score (7). Motor nerve conduction veloc- nerve dysfunction. The minimal criteria sectional area of all muscles was estimated ity and response amplitudes were deter- for diabetic neuropathy were adopted and

DIABETES CARE, VOLUME 27, NUMBER 10, OCTOBER 2004 2383 Atrophy of foot muscles in diabetic neuropathy

lationship between degree of atrophy and degree of neuropathy based on clinical, electrophysiological, and quantitative sensory examinations. Loss of sensation, toe abnormalities, and foot ulcers are easily recognized at the clinical examination of a diabetic foot. In contrast, evaluation of the motor system is hampered by the inability to evaluate the strength of foot muscles and difficulties estimating muscle mass. In a previous study of diabetic patients, we have found a very close relationship between the volume of muscles and strength of ankle dor- sal and plantar flexors (r values Ͼ0.8) (3). This clearly indicates that determination of muscle mass reflects motor function. In healthy subjects, r values between muscle strength and total muscle volume ex- Figure 2—The relationship between the neuropathy rank-sum score and the volume of foot ceeded 0.85, a slightly closer relation than muscles in all diabetic patients given as a percentage of their individually matched control values the one between muscle cross-sectional (r ϭϪ0.75, P Ͻ 0.0001). area and muscle strength (4). Volume of striated muscles in the foot was determined using a stereological applied for separation of neuropathic and with neuropathy is one-half that of con- point-counting method (8). This method nonneuropathic patients (1). trol subjects and also one-half that of di- provides an unbiased estimation of the Statistical comparisons between abetic patients without neuropathy. volume of any structure of interest within groups were made with ANOVA, and cor- Expressed relative to their individually an object pending unequivocal definition relations were sought for using linear re- matched control subjects, the median of the structure, irrespective of the form of gression analysis. VFMs were 49% (range 11–95) and 106% the object. In this study, none of the pa- (range 70–130), respectively (P Ͻ 0.01). tients had any significant foot or toe de- RESULTS — The diabetic patients had In the combined group of diabetic pa- formity. Therefore, a similar orientation a median neurological impairment score tients with and without neuropathy, there of the cross-sectional scans is obtained in of 7 (range 0–36). According to the min- was a close relationship between the neu- the two groups, thereby providing repre- imal criteria for diabetic neuropathy, 15 ropathy rank-sum score and the VFM sentative views of the striated muscles in and 8 patients were defined as neuro- (Fig. 2). Furthermore, the VFM was both patients and control subjects. pathic and nonneuropathic, respectively. closely related to the amplitude of the Recently, using MRI in a group of Patients with and without neuropathy compound muscle action potential of the neuropathic patients, Bus et al. (9) ob- had a diabetes duration of 30 (range 21– peroneal nerve (r ϭ 0.71, P Ͻ 0.001), served considerable loss of small foot 38) and 27 years (range 16–35), respec- whereas no statistically significant rela- muscles compared with nondiabetic con- tively (P ϭ NS). Thirteen patients had tion was found between the VFM and the trol subjects. Their study did not include symptoms of peripheral neuropathy. All motor nerve conduction velocity of the a group of nonneuropathic diabetic pa- had sensory complaints, with paresthesia peroneal nerve (r ϭ 0.42, P ϭ 0.06). No tients. We found completely preserved and/or loss of sensation in the lower ex- relationship was found between the muscle volume in long-term diabetic pa- tremities. In addition, two patients had VFM and duration of diabetes (r ϭ 0.19, tients without neuropathy. Despite differ- neurogenic pain, and six men complained P ϭ 0.39). ences in patient selection and techniques of erectile dysfunction. Only three pa- for quantification of muscle mass, the tients had motor symptoms, all of which CONCLUSIONS — Applying MRI finding of Bus et al. is in accordance with involved the ankles. Motor nerve conduc- and a stereological point-counting the present observation, emphasizing that tion velocity of the median and peroneal method, we found that total VFM is diabetic patients with chronic neuropathy nerves was 48.2 m/s (range 41.3–61.0) halved in diabetic patients with chronic have considerable loss of striated muscle and 37.1 m/s (range 20.8–45.6), respec- neuropathy as compared with that of in the feet. Atrophy of foot muscles is be- tively. In three patients, no response nonneuropathic diabetic patients and lieved to result in altered architecture could be obtained from the extensor digi- nondiabetic control subjects. In the most of the foot and can thereby cause toe ab- torum brevis muscle. advanced cases of neuropathy, volume normalities (clawing, hammering) (10). In Fig. 1, volume of the intrinsic foot was Ͻ20% of that of individual control Together with sensory loss, this will lead muscles (VFM), together with an illustra- values. Our hypothesis that atrophy of in- to callus formation and ultimately to foot tive example of a cross-section of the foot, trinsic foot muscles is a measure closely ulcers. Interestingly, in the study by Buss is shown for each of the three groups. It reflecting motor dysfunction in diabetic et al. some patients had atrophy without appears that the VFM of diabetic patients neuropathy is supported by the close re- toe deformities, whereas the opposite was

2384 DIABETES CARE, VOLUME 27, NUMBER 10, OCTOBER 2004 Andersen, Gjerstad, and Jakobsen not the case. In our study, no patient vance of quantitating foot muscle atrophy cal techniques. J Appl Physiol 86:1670– had any significant foot or toe deformity. in relation to other neuropathic manifes- 1675, 1999 This supports the notion that loss of foot tations. Because MRI is a relatively time- 6. Dyck PJ, Sherman WR, Hallcher LM, Ser- muscles precedes development of toe consuming and expensive technique, an vice FJ, O’Brien PC, Grina LA, Palumbo abnormalities. easier-to-perform evaluation of muscle PJ, Swanson CJ: Human diabetic endo- neurial sorbitol, fructose, and myo-inosi- Ultrasonography has been applied volume is needed. tol related to sural nerve morphometry. more frequently than MRI in studies of Ann Neurol 8:590–596, 1980 the diabetic foot. An inverse relationship 7. Dyck PJ: Quantitating severity of neurop- has been found between the plantar fascia Acknowledgments— This study was supported in part by the Karen Elise Jensen Foun- athy. In Peripheral Neuropathy. 3rd ed. thickness and the dynamic foot pressure dation, the Research Initiative of Aarhus Dyck PJ, Thomas PK, Griffin JW, Low PA, (11), and changes in the structure of the University Hospital, and the Danish Diabetes Poduslo JF, Eds. Saunders, Philadelphia, plantar fascia seem to influence the joint Association. 1993, p. 686–697 mobility of the first metatarsophalangeal 8. Gundersen HJ, Jensen EB: The efficiency joint (12). No ultrasonographic study has of systematic sampling in stereology and its prediction. J Microcr 147:229–263, been performed to quantify the amount of References 1. Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, 1987 striated muscles in the diabetic foot. 9. Bus SA, Yang QX, Wang JH, Smith MB, In patients with peripheral arterial oc- Klein R, Pach JM, Wilson DM, O’Brien PC, Melton LJ 3rd, Service FJ: The preva- Wunderlich R, Cavanagh PR: Intrinsic clusive disease, strength of the dorsiflex- lence by staged severity of various types muscle atrophy and toe deformity in the ors is reduced compared with age- of diabetic neuropathy, retinopathy, and diabetic neuropathic foot: a magnetic res- matched control subjects (13) and nephropathy in a population-based co- onance imaging study. Diabetes Care 25: atrophy of muscle fibers can occur. Dia- hort: the Rochester Diabetic Neuropathy 1444–1450, 2002 betic patients often have macrovascular Study. Neurology 43:817–824, 1993 10. Boulton AJ: The pathogenesis of diabetic complications that could contribute to 2. Thomas PK, Tomlinson DR: Diabetic and foot problems: an overview. Diabet Med such atrophy. However, in this study hypoglycemic neuropathy. In Peripheral 13 (Suppl. 1):S12–S16, 1996 11. Abouaesha F, van Schie CH, Griffths none of the patients had intermittent Neuropathy. 3rd ed. Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo JF, Eds. GD, Young RJ, Boulton AJ: Plantar tissue claudication, all walked independently, Saunders, Philadelphia, 1993, p. 1219– thickness is related to peak plantar pres- and none had a history of foot ulcers. Fur- 1250 sure in the high-risk diabetic foot. Diabe- thermore, the median age of the patients 3. Andersen H, Gadeberg PC, Brock B, Ja- tes Care 24:1270–1274, 2001 was only 47 years, which makes arterial kobsen J: Muscular atrophy in diabetic 12. D’Ambrogi E, Giurato L, D’Agostino MA, insufficiency and physical inactivity an neuropathy: a stereological magnetic res- Giacomozzi C, Macellari V, Caselli A, Uc- unlikely explanation for the profound at- onance imaging study. Diabetologia 40: cioli L: Contribution of plantar fascia to rophy observed. 1062–1069, 1997 the increased forefoot pressures in dia- In conclusion, quantification of foot 4. Brash PD, Foster J, Vennart W, Anthony betic patients. Diabetes Care 26:1525– muscles enables an objective measure of P, Tooke JE: Magnetic resonance imaging 1529, 2003 techniques demonstrate soft tissue dam- 13. Scott-Okafor HR, Silver KK, Parker J, motor dysfunction closely related to the age in the diabetic foot. Diabet Med 16: Almy-Albert T, Gardner AW: Lower ex- severity of diabetic neuropathy. Monitor- 55–61, 1999 tremity strength deficits in peripheral ing of VFM may be helpful in treatment 5. Gadeberg P, Andersen H, Jakobsen J: arterial occlusive disease patients with trials. However, larger-scaled prospective Volume of ankle dorsiflexors and plan- intermittent claudication. Angiology 52:7– studies are needed to elucidate the rele- tar flexors determined with stereologi- 14, 2001

DIABETES CARE, VOLUME 27, NUMBER 10, OCTOBER 2004 2385