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LETTERS TO THE EDITOR
Year : 2022  |  Volume : 25  |  Issue : 6  |  Page : 1184-1187
 

Muscle MRI-Based atrophy pattern recognition: Notable findings in a case of pathologically proven lipid storage myopathy


1 Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India
2 Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India
3 Department of Neuroradiology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India

Date of Submission18-May-2022
Date of Decision22-Jun-2022
Date of Acceptance24-Jun-2022
Date of Web Publication04-Nov-2022

Correspondence Address:
Ameya Patwardhan
Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.aian_447_22

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How to cite this article:
Patwardhan A, Mukherjee J, Mhatre R, Lanka V, Asranna A, Tiwari R, Sriram N, Kulanthaivelu K, Mahadevan A, Ramakrishnan S. Muscle MRI-Based atrophy pattern recognition: Notable findings in a case of pathologically proven lipid storage myopathy. Ann Indian Acad Neurol 2022;25:1184-7

How to cite this URL:
Patwardhan A, Mukherjee J, Mhatre R, Lanka V, Asranna A, Tiwari R, Sriram N, Kulanthaivelu K, Mahadevan A, Ramakrishnan S. Muscle MRI-Based atrophy pattern recognition: Notable findings in a case of pathologically proven lipid storage myopathy. Ann Indian Acad Neurol [serial online] 2022 [cited 2023 Jan 29];25:1184-7. Available from: https://www.annalsofian.org/text.asp?2022/25/6/1184/360463




Sir,

Lipid storage myopathy is a group of rare multi-system disorders usually caused by enzymatic defects in lipid metabolism. They may manifest at all ages, from early stages of life to late adulthood, and may have an acute or a chronic presentation. They commonly affect the skeletal muscle but may involve other organ systems as well.[1] In most myopathic forms of the disease, deposition of lipid in muscle fibers is found on muscle biopsy specimens. Although rare, it is essential to recognize these disorders as they are potentially treatable and mimic other disorders, including inflammatory myopathies and even polyradiculopathy, with important therapeutic implications.[2] We report a case of lipid storage myopathy in which a systematic diagnostic approach and investigations including muscle magnetic resonance imaging (MRI) and muscle biopsy greatly aided the diagnosis, especially as genetic testing was not feasible.


   Case Report Top


An 18-year-old girl from South India, born of a second-degree consanguineous parentage, presented to the neurology emergency services with acute onset and gradually progressive, proximal predominant weakness of both lower limbs. She had dull aching pain of moderate intensity over both thighs since the onset of weakness. There was no history of fever, loose motions, vomiting, abdominal pain, prolonged exercise, or fasting before the beginning of the illness. She had no history of similar episodes or a family history of similar illness. On examination, she had severe neck flexor weakness along with severe proximal muscle weakness of the lower limbs without an upper limb or craniobulbar involvement. She had hyporeflexia in the lower limb.

Investigations showed a marked rise in CK (45433 U/L), Serum glutamic pyruvic transaminase (SGPT) (691 U/L), Serum glutamic oxaloacetic transaminase (SGOT) (5665 U/L), and Lactate dehydrogenase (LDH) (10164 U/L), and myoglobinuria was present. Nerve conduction studies and electromyography of the affected muscles were normal. Blood investigations, including hemogram, peripheral smear, serum bilirubin, alkaline phosphatase, renal function, serum electrolytes, thyroid profile, autoimmune markers, myositis profile, HBsAg, and HIV were negative. Chest X-ray and ultrasound of the abdomen were normal. The lipid profile showed mildly elevated total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol with normal very-low-density lipoprotein cholesterol and triglyceride levels. Cardiac evaluation with echocardiography and 2D ECHO was normal. The non-ischemic forearm exercise test showed normal elevation of ammonia and lactate from the baseline [Figure 1].
Figure 1: Normal elevation of ammonia and lactate levels from the baseline

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MRI of lower limbs [Figure 2] showed heterogeneous but symmetric T2/short tau inversion recovery (STIR) hyperintense signal changes and swelling in the bilateral abdominal wall muscles, paraspinal muscles, psoas muscles, gluteal muscles, anterior thigh compartment muscles (with sparing of rectus femoris), hamstring muscles (with sparing of the semitendinosus), thigh adductor compartment muscles (with sparing of gracilis), and the muscles of the deep posterior compartment of the leg. Patchy thickening and hyperintensity were also noted in the intermuscular fascial septa and superficial fasciae (most pronounced in the anterior thigh compartment). Minimal fatty infiltration was also noted in the deep posterior compartment muscles of the right calf. Symmetric proximal muscle predominant edematous changes led to a differential diagnosis of autoimmune myositis vs acutely decompensated metabolic/drug-induced rhabdomyolysis. TMS showed low levels of free carnitine and long-chain acyl-carnitines in blood. Muscle biopsy performed from the left quadriceps revealed preserved fascicular architecture with scattered myofibers showing fine cytoplasmic vacuolation, without any active myopathic features or inflammation. Hypermetabolic fibers were seen on nicotinamide adenine dinucleotide (NADH) and succinate dehydrogenase (SDH) stains. Periodic acid Schiff (PAS) stain did not detect any glycogen deposits. Cytoplasmic vacuoles were stained positive with Oil Red O, predominantly involving type 1 fibers, suggestive of lipid storage disease [Figure 3]. A diagnosis of primary carnitine deficiency was considered. The patient was treated with immediate hydration, intravenous, and oral dextrose, after which the patient showed rapid improvement in muscle power within 48 hours and creatine kinase reduced to 2399 U/L in 1 week.
Figure 2: Muscle MRI findings. Axial sections of the lower abdomen (a and b), mid-pelvis (c and d), upper thigh at the level of the femoral triangle (e and f), lower thigh at the level of the Hunter canal (g and h), and the mid-calf (i and j) have been shown. (a, c, e, g, and i) represent STIR acquisitions; (b, d, f, h, and j) represent non-fat-saturated T1 weighted images (T1WI). Heterogeneous but symmetric STIR hyperintense signal changes and swelling are noted in the bilateral abdominal wall muscles (short arrow, (a), paraspinal muscles (long arrow, (a)), psoas muscles (arrowhead), (b), gluteal muscles (4w, (c)), anterior thigh compartment muscles (long arrows (e and g)) (with sparing of rectus femoris—right-angled arrow, (g), hamstring muscles (short arrow, (g)) (with sparing of the semitendinosus—curved arrow, (g), thigh adductor compartment muscles (arrowhead, (g)) (with sparing of gracilis—double curved arrow, (g) and the muscles of the deep posterior compartment of the leg (short arrow, (i)). Patchy thickening and hyperintensity are also noted in the intermuscular fascial septa and superficial fasciae (most pronounced in the anterior thigh compartment best appreciated in (e and g)). Corresponding T1WI show minimal fatty infiltration in the deep posterior compartment muscles of the right calf (long arrow, (j)). Rest of the involved muscle groups show no significant fatty infiltration or atrophy (b, d, f, h, j)

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Figure 3: Muscle biopsy shows fine cytoplasmic vacuoles within several myofibers (asterisk, a). There was no evidence of ragged red fibers on modified Gomori trichrome (MGT) (b). The fibers with vacuoles showed accumulations of lipid droplets on Oil Red O stain (asterisk, c) and were hypermetabolic on nicotinamide adenine dinucleotide (NADH) (asterisk, d) and succinate dehydrogenase (SDH) (asterisk, e) stains. Mosaic pattern of fiber typing was seen on ATPase at pH 9.4 (f)

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   Discussion Top


Lipid storage disorders are a group of disorders caused by defects in the metabolic pathways of fatty acid transport and oxidation. Plasma-free fatty acids derived from adipose tissue serve as the source of energy for skeletal muscle during rest and sustained exercise. A wide spectrum of clinical syndromes are associated with disorders of lipid metabolism and may involve skeletal muscles, cardiac muscles, and other organ systems. They may present from early infancy and childhood to even late adulthood.[3]

Skeletal muscle involvement in these groups of disorders can be in the form of a progressive myopathy with a chronic course or may have fluctuating muscle weakness with acute exacerbations leading to rhabdomyolysis, triggered by several factors such as exercise or fasting. Our patient had an acute presentation of myopathy, but no antecedent precipitating factors were found.

Acute onset of weakness combined with the clinical findings of proximal lower limb and neck flexor weakness with hyporeflexia in the lower limbs initially led to clinical suspicion of Guillain Barre syndrome (GBS). The absence of cranial nerve involvement and a disproportionate amount of pain, however, were odd features. The serum creatine kinase levels were extremely high, and this raised a red flag against the diagnosis of GBS and the presence of an underlying myopathic process. Further evaluation was directed toward the identification of the cause of myopathy.

The presence of myoglobin in urine was suggestive of rhabdomyolysis; however, renal parameters were normal. Elevated liver enzymes (SGOT) were likely due to elevated muscle isoform of the enzyme. The non-ischemic forearm exercise test is a useful investigation with high sensitivity and specificity to detect disorders of glycogen metabolism.[4] Normal elevation of ammonia and lactate levels from the baseline on the non-ischemic forearm exercise test [Figure 1] made the possibility of carbohydrate metabolism disorder as a cause of metabolic myopathy less likely in our case.

TMS is a useful screening test that indicates the presence of several metabolic disorders.[5] Low levels of free carnitine and long-chain acyl-carnitine in the blood were seen on TMS, suggestive of a lipid storage disease involving carnitine metabolism as the underlying cause. Our patient is likely to have a primary carnitine deficiency as there was no history of chronic medication, malnutrition, or renal disease, causing the reduced value of both free carnitine and long-chain acylcarnitine.

Muscle MRI-based atrophy pattern recognition has well-established roles in the differential diagnosis of inherited muscle disorders.[6] However, muscle patterns of acute inflammation and edema have offered little discriminatory value in acute myopathies. Inflammation secondary to infection, radiation, and trauma tends to be asymmetric as a reflection of the inciting insult.[7] Symmetric proximal muscle edema, however, invokes a broad differential diagnosis of inflammatory myopathy vs acutely decompensated metabolic/drug-induced rhabdomyolysis.[7] Further differentiation requires corroboration with biochemistry and biopsy.

Rhabdomyolysis in primary carnitine deficiency is likely a manifestation of acute energy failure secondary to the underlying fatty acid β-oxidation defect.[8] Large proximal muscles with predominantly red (type 1) fibers have a higher dependence on fatty acid oxidation than smaller muscles, [primarily white (type 2) fibers] which depend solely on faster glucose metabolism. Findings of our muscle biopsy, as well as the previous descriptions of this disorder, have in fact documented this relative selectivity for the involvement of type 1 fibers.[8] Findings in our case-symmetric involvement of large proximal thigh muscles and deep posterior compartment leg muscles, along with peculiar sparing of smaller muscles of the thigh (rectus femoris, gracilis, and semitendinosus), are likely a reflection of these differences in fiber distribution and metabolism.[9],[10] Determining the specificity of these findings, however, requires larger data sets.

Previous accounts of imaging in primary carnitine deficiency have described the involvement of the white matter of frontal lobes, the caudate nucleus, and the cerebellum;[11] however, muscle MRI findings have not been described before. Of note, selective involvement of the posterior compartment of the leg and relative sparing of small muscles of the thigh (semitendinosus and gracilis) are findings which have also been documented in neutral lipid storage disease with myopathy, a disorder with a similar pathophysiological basis.[12]

Muscle biopsy findings in lipid storage myopathy range from normal histology to vacuolar myopathy. The appearance of these vacuoles and demonstration of storage materials with special stains help to differentiate between the causes of vacuolar myopathy. Lipid storage disorders demonstrate fine vacuoles with Oil Red O positive lipid droplets predominantly involving type 1 fibers. In contrast, glycogen storage disorders show coarse vacuoles which are PAS-positive but sensitive to diastase, suggestive of glycogen deposits. In addition, oxidative stains (NADH and SDH) demonstrate the presence of hypermetabolic fibers in lipid storage disorders. Secondary mitochondrial abnormalities in the form of ragged red fibers and Cyclooxygenase (COX)-deficient fibers may also be seen in primary carnitine deficiency. In such situations, clinicopathological correlation and the use of ancillary tests become crucial for the diagnosis. Our case did not show features of mitochondrial myopathy. Muscle biopsy findings provide useful evidence of lipid accumulation in the muscle, highlighting its role in the diagnosis of metabolic myopathies, especially when the genetic diagnosis may not be feasible. The findings in our case were similar to previous case reports of primary carnitine deficiency myopathy.[8],[13]

Genetic testing has an important role in confirming the diagnosis of lipid storage myopathies, especially when TMS and muscle biopsy show inconclusive results. Recently, a case series of 11 genetically proven lipid storage myopathy from India demonstrated the mutational and phenotypic diversity seen in these cases.[13] Pathogenic recessive mutations were commonly found in the gene for electron transport flavoprotein dehydrogenase (ETFDH), followed by carnitine palmitoyl transferase II (CPT2), flavin adenine dinucleotide synthetase1 (FLAD1), very long-chain acyl CoA dehydrogenase (ACADVL), and patatin-like phospholipase domain containing 2 (PNPLA2).[13]

Genetic testing for lipid storage myopathies should be considered in patients with limb-girdle weakness and exercise-induced myalgias as TMS and muscle biopsy may not show abnormalities in all cases.

Treatment of acute presentations causing rhabdomyolysis involves prompt supportive therapy with hydration and supplementation of dextrose.[14] Our patient had a clinical response to supportive therapy, and acute complications of rhabdomyolysis were prevented.


   Conclusion Top


This case demonstrates a systematic diagnostic approach for the evaluation of a case with suspected metabolic myopathy. It also highlights the notable muscle MRI atrophy patterns in pathologically proven lipid storage myopathy. A larger data set is required to determine the specificity of the muscle MRI findings. Muscle MRI and muscle biopsy have an important role in the diagnosis, especially when genetic testing is not feasible.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Ethics approval

Not Applicable.

Consent for publication

Not Applicable.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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El-Gharbawy A, Vockley J. Inborn errors of metabolism with myopathy: Defects of fatty acid oxidation and the carnitine shuttle system. Pediatr Clin North Am 2018;65:317-35.  Back to cited text no. 3
    
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Hogrel JY, Laforêt P, Ben Yaou R, Chevrot M, Eymard B, Lombès A. A non-ischemic forearm exercise test for the screening of patients with exercise intolerance. Neurology 2001;56:1733-8.  Back to cited text no. 4
    
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Vengalil S, Preethish-Kumar V, Polavarapu K, Christopher R, Gayathri N, Natarajan A, et al. Fatty acid oxidation defects presenting as primary myopathy and prominent dropped head syndrome. Neuromuscul Disord NMD 2017;27:986-96.  Back to cited text no. 5
    
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Wattjes MP, Kley RA, Fischer D. Neuromuscular imaging in inherited muscle diseases. Eur Radiol 2010;20:2447-60.  Back to cited text no. 6
    
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Lötscher J, Kovacs BK, Walker UA. Making the diagnosis of myositis: Muscle MRI. In: Aggarwal R, Oddis CV, editors. Managing Myositis: A Practical Guide. Cham: Springer International Publishing; 2020. p. 145-60. Available from: https://doi.org/10.1007/978-3-030-15820-0_16.  Back to cited text no. 7
    
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Vielhaber S, Feistner H, Weis J, Kreuder J, Sailer M, Schröder JM, et al. Primary carnitine deficiency: Adult onset lipid storage myopathy with a mild clinical course. J Clin Neurosci Off J Neurosurg Soc Australas 2004;11:919-24.  Back to cited text no. 8
    
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Gollnick PD, Sjödin B, Karlsson J, Jansson E, Saltin B. Human soleus muscle: A comparison of fiber composition and enzyme activities with other leg muscles. Pflüg Arch 1974;348:247-55.  Back to cited text no. 9
    
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Edgerton VR, Smith JL, Simpson DR. Muscle fibre type populations of human leg muscles. Histochem J 1975;7:259-66.  Back to cited text no. 10
    
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Mahale RR, Mehta A, Timmappaya A, Srinivasa R. Primary carnitine deficiency as a cause of metabolic leukoencephalopathy: Report of one case. Neurol India 2016;64:166.  Back to cited text no. 11
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Zhang W, Wen B, Lu J, Zhao Y, Hong D, Zhao Z, et al. Neutral lipid storage disease with myopathy in China: A large multicentric cohort study. Orphanet J Rare Dis 2019;14:234.  Back to cited text no. 12
    
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Vengalil S, Polavarapu K, Preethish-Kumar V, Nashi S, Arunachal G, Chawla T, et al. Mutation spectrum of primary lipid storage myopathies. Ann Indian Acad Neurol 2022;25:106-13.  Back to cited text no. 13
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Karmaniolas K, Ioannidis P, Liatis S, Dalamanga M, Papalambros T, Migdalis I. Primary carnitine deficiency in a male adult. J Med 2002;33:105-10.  Back to cited text no. 14
    


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