Abstract
Denervation pseudohypertrophy is an important and well described, albeit rare, cause of limb swelling that is seldom encountered in the clinical setting. Careful history taking, reasonable clinical suspicion, and referral for magnetic resonance imaging are crucial to arriving at the diagnosis and recommending appropriate treatment. Although typically a slow, insidious process, we report a rare case of acute denervation pseudohypertrophy in a 76-year-old male with diabetic neuropathy, chronic venous insufficiency, and remote tibial fracture repair. Magnetic resonance imaging findings were significant for bilateral denervation pseudohypertrophy of the left greater than right calf muscles with associated diabetic neuropathy. We postulated that the latter is likely the main underlying etiology, particularly given the magnetic resonance imaging’s bilateral findings. The case highlights the importance of considering denervation pseudohypertrophy in the differential diagnosis of acute limb swelling despite its rarity.
Keywords
Introduction
Denervation pseudohypertrophy is an uncommon cause of unilateral limb swelling characterized by muscular enlargement due to the accumulation of adipose tissue between muscle fibers resulting from partial muscle denervation.1,2 Although the expected response to denervation typically involves atrophy of the affected muscle, in some rare instances, chronic or partial denervation may instead produce a paradoxical pseudohypertrophy, characterized by muscle enlargement with fatty infiltration. 3 Denervation pseudohypertrophy classically presents with painless palpable edema of the involved muscle, though clinical presentation may vary and include pain, weakness, erythema, and sensory deficits. 1 The phenomenon has been associated with various neurological insults, including traumatic nerve injury, chronic radiculopathy, anterior horn cell disorders like poliomyelitis, and peripheral neuropathies such as diabetic neuropathy.1,2 Diabetic neuropathy has been especially highlighted as a cause of denervation pseudohypertrophy as part of the long-term sequela of hyperglycemia-induced nerve injury. 3 Magnetic resonance imaging (MRI) findings often depict diffuse fatty infiltration of the gastrocnemius and soleus muscles with preserved muscle architecture, a finding that has been emphasized in contemporary reports in affected patients.2–4 Previous studies have highlighted that denervation pseudohypertrophy frequently mimics more common etiologies of unilateral limb swelling such as deep vein thrombosis (DVT), infection, or soft tissue tumors, underscoring the importance of suspecting the diagnosis in the appropriate clinical context, and recognizing its characteristic imaging features. 4
To date, there have been no epidemiological studies documenting the true incidence of the diagnosis due to its exceeding rarity. Much of what is known about denervation pseudohypertrophy stems from isolated case reports and limited case series.1–6 Although most cases described in the literature follow a chronic, insidious course, some recent reports demonstrate that denervation-related pseudohypertrophy can present subacutely, or even precede overt neurological deficits. 5 The present report highlights the clinical presentation, imaging findings, and diagnostic considerations in a patient encountered in the outpatient primary care office who demonstrated an unusually acute presentation of denervation pseudohypertrophy in the setting of underlying diabetic neuropathy, chronic venous insufficiency, and a decades-long history of ipsilateral limb trauma from a motor vehicle collision.
Case
We present the case of a 76-year-old male with a past medical history of essential hypertension, hyperlipidemia, type 2 diabetes mellitus, chronic venous insufficiency, coronary artery disease, and gastroesophageal reflux disease who presented to the outpatient primary care office 2 days after developing an acute onset of left calf pain. He reported that two nights before, he was awakened with sharp, intense left calf pain that was 8/10 in severity, which lasted for several hours. The pain began in the calf but quickly radiated to the entire leg, including the ankle and foot, with associated swelling and hyperthermia of the leg, particularly the calf. There was also numbness and paresthesia of the calf and distal leg. The patient denied any inciting event or precipitating injury, and he had never experienced anything similar in the past. He initially delayed seeking medical attention, thinking his symptoms were related to his chronic venous insufficiency, which has caused him intermittent painless lower extremity swelling for many years. However, when the pain and its associated symptoms persisted, he decided to present to the primary care clinic. The pain was exacerbated by standing and alleviated by leg elevation. He denied tenderness to touch, fever, and erythema. He also denied chest pain, shortness of breath, syncope, presyncope, and any other alarming symptoms. The pain had subsided to a 6/10 on the day of presentation but continued to linger over the next 4 weeks, eventually resolving without intervention.
Of note, the patient was involved in a motor vehicle collision in 1970, after which he underwent open reduction and internal fixation of the left distal tibia to repair a fracture with the placement of a metal plate. He denied any postoperative complications or any similar acute episodes of left leg pain in the past. In addition, the patient also had a history of two varicose vein surgeries on his left lower extremity 6–10 years ago. He was on daily antiplatelet therapy with 75 mg of clopidogrel for a cardiac stent, with which he was compliant.
On physical examination, all vital signs were within normal limits. The patient’s left calf had a measured circumference of 39 cm, while the right calf was 34 cm (circumferences were measured 15 cm below the patellar ligament). There was significant erythema to the calf and the remainder of the leg and foot. The left calf and ankle were tender to palpation, and the calf, ankle, and foot were warm to the touch. There was visible asymmetric swelling of the left lower extremity compared to the right. The neurological examination was unremarkable. No other abnormalities were noted on physical examination.
The patient was sent for urgent lab workup with a complete blood count and a complete metabolic panel, which were remarkable only for a random glucose of 140 mg/dL. The patient’s hemoglobin A1c had been stable at 7.4%, and he had been maintaining good compliance with his oral glycemic management. Given the patient’s enlarged left calf circumference, he was also urgently sent to undergo a venous duplex ultrasound of the lower extremity to evaluate for a DVT. The ultrasound was negative for DVT, and the radiologist recommended ordering an MRI without contrast of the lower extremities for further investigation. The MRI revealed bilateral denervation pseudohypertrophy of the left greater than right medial gastrocnemius and, to a lesser extent, the left soleus muscles, with associated diabetic neuropathy (Figure 1). The remaining muscles were spared. There was also nonspecific circumferential subcutaneous and perifascial soft tissue edema of the mid to distal left lower leg, likely due to underlying chronic venous insufficiency. Superficial subcutaneous varicosities were also noted medially in the proximal to mid-lower leg.
MRI (GE Signa HDX23, 1.5 Tesla) of the patient’s legs obtained 48 h after initial presentation. (a) Axial T1-weighted image (TR = 172 ms, TE = 8.3 ms). (b) Axial T2-weighted fat-saturated image (TR = 4418 ms, TE = 57.7 ms) of the left proximal lower leg/calf. (c) Coronal T1-weighted image (TR = 447 ms, TE = 8.2 ms). (d) Coronal T2-weighted fat-saturated image (TR = 3875 ms, TE = 47.3 ms) of both lower legs. Imaging shows asymmetric enlargement with high signal (T1) and low signal (T2) intensity of the medial gastrocnemius muscle (left significantly worse than right), consistent with fatty pseudohypertrophy. Incidental mild subcutaneous and perifascial soft tissue edema are also present, likely due to underlying chronic venous insufficiency. Blue arrows denote asymmetrically enlarged left medial gastrocnemius muscle.
Denervation pseudohypertrophy is a rare cause of acute unilateral leg swelling and pain; thus, a multidisciplinary approach was adopted in formulating a treatment plan. The primary care office consulted radiology, neurology, orthopedics, physical medicine and rehabilitation, and vascular surgery specialists to discuss the case, and all agreed that physical therapy is the most suitable next step. The patient, having already experienced a slight improvement in symptoms without intervention, expressed hesitation regarding physical therapy, believing that he would not benefit from it. However, he remained open to trying physical therapy if his pain worsened. The patient’s wishes were respected, and he was encouraged to notify his primary care team should his pain recur or worsen. To date, the patient has not experienced a recurrence, and his left leg has been consistently pain-free with occasional mild swelling from chronic venous insufficiency, unchanged from his previous status (Table 1).
Case timeline as denoted by important dates, diagnostic events, and clinical course.
CBC: complete blood count; CMP: complete metabolic panel; DVT: deep vein thrombosis; HbA1c, hemoglobin A1c; MRI: magnetic resonance imaging; PM&R: Physical medicine and rehabilitation; UTSW: University of Texas Southwestern.
Patient perspective
The patient was understandably worried about his symptoms at the initial presentation, particularly due to their relatively acute onset. He had been in his usual state of health prior to the stated episode. He worked proactively and cooperatively with members of the treatment team, obtaining the recommended labs and imaging studies promptly. He maintained a positive and hopeful demeanor throughout his clinical course.
Discussion
Denervation pseudohypertrophy is characterized by unilateral limb swelling that can present diagnostic challenges, particularly due to the condition’s rarity. This case highlights several important aspects of denervation pseudohypertrophy and its clinical presentation.
Etiology and pathophysiology
Denervation pseudohypertrophy results from partial muscle denervation, the etiology of which may range from peripheral neuropathies and spinal radiculopathies to spina bifida, peripheral nerve injuries, and motor neuron disease.1,2 The postulated pathophysiology involves the reduction of muscle fiber size secondary to denervation, which reduces muscular tension and stimulates pluripotent mesodermal cells to differentiate into lipocytes, resulting in fatty infiltration. 7 Most cases occur through a chronic, long-standing, and often insidious process. Some acute-onset cases have been reported, though this has been exceedingly rare.
The etiology of the described patient’s denervation pseudohypertrophy was likely multifactorial, with diabetic neuropathy likely playing a significant role. Diabetic neuropathy is a well-established cause of denervation changes in muscles, including pseudohypertrophy. 6 Recent MRI-based systematic review data show that patients with diabetic neuropathy demonstrate substantially greater intramuscular fat infiltration and sarcopenic change compared with non-neuropathic diabetic patients, supporting a strong mechanistic link between neuropathy and muscle degeneration. 8 Partial denervation leads to fatty infiltration of muscle fibers, resulting in enlargement without true hypertrophy.9,10 Contemporary case reports further demonstrate that partial denervation from neuropathy, radiculopathy, or peripheral nerve compression consistently produces this fatty replacement pattern on MRI.3,11
The patient’s history of trauma to the left leg from his motor vehicle collision in 1970 is an interesting component of the case, as it may have played a potential role in the pathogenesis of his condition. His fracture of the left distal tibia may have resulted in some level of peripheral nerve injury or compression, which is another documented cause of denervation pseudohypertrophy.2,12 Recent radiculopathy-associated pseudohypertrophy cases describe identical patterns of fatty infiltration and asymmetric calf enlargement due to chronic neurogenic injury, reinforcing the plausibility of remote nerve trauma contributing to pseudohypertrophy. 5 However, the length of time between the motor vehicle collision and the date of presentation (over 50 years), and the acute and rapid development of his symptoms, make this a less likely culprit.
Clinical presentation
The acute onset of pain and swelling in the described case is atypical for denervation pseudohypertrophy, which usually develops gradually and in a more stepwise or progressive fashion. 9 Most prior reports have described pseudohypertrophy as a process evolving over months to years, as for example, in recent cases of athletes and patients with chronic radiculopathy who presented with 2–3 years of progressive limb enlargement before diagnosis.4,11 This acute presentation, associated with a significant enlargement of the patient’s left calf compared to the right, initially led the team to consider more urgent conditions, such as DVT. The patient’s comorbidities, including a history of chronic venous insufficiency and type 2 diabetes mellitus, along with his previous left-sided varicose vein surgeries, further complicated the clinical picture. The case underscores the importance of maintaining a broad differential diagnosis when evaluating unilateral limb swelling, especially in patients with known vascular conditions.
Diagnostic approach
The use of MRI was crucial in reaching the correct diagnosis. MRI is the gold standard for identifying denervation pseudohypertrophy, typically revealing characteristic findings of muscle enlargement with interspersed fat.8,9,13 The present MRI findings in this case of increased muscle volume, well-defined margins, and normal contour, along with an excessive amount of fat interspersed throughout normal muscle, were consistent with a pseudohypertrophy diagnosis. 8 Electromyography (EMG) and nerve conduction studies could serve an important role in diagnosis; however, neither was pursued, given that the MRI was confirmatory. While a confirmatory muscle biopsy was likewise not performed, biopsy-confirmed cases in the literature have demonstrated identical MRI–histopathology correlation, showing atrophic fibers intermixed with mature adipocytes replacing muscle tissue as would be expected. 4
The differential diagnosis of an acute-onset unilateral limb swelling is broad. Among the most common and potentially life-threatening conditions is DVT, which presents with acute pain, warmth, erythema, and asymmetric calf swelling. This condition must be considered early because timely treatment is paramount to prevent embolization, particularly to pulmonary vessels, which is a significant cause of morbidity and mortality. A venous Doppler ultrasound is a quick and effective method to rule in or out DVT, which was the first diagnostic step that the patient underwent.
Cellulitis, or another soft tissue infection, is also a common cause of unilateral limb swelling and will usually present with warmth, erythema, and edema of the infection site with poorly demarcated borders. History and physical examination may provide clues leading to this diagnosis, for example, evidence of skin disruption from an open wound, insect bite, or stasis edema, which could serve as a nidus for infection. The patient has chronic venous insufficiency, which increases his risk of soft tissue skin infections as it predisposes him to stasis edema, which may progress to ulceration and infection. However, the patient’s swelling was more proximal than would be expected in venous insufficiency, his pain was maximal at onset, and he reported subjective leg weakness, all of which would be unusual for an infectious process.
Similarly, muscular tumors or lipomas should be considered in patients presenting with unusual unilateral limb swelling. However, progression would be expected to be much slower, assuming a chronic rather than acute course. This aligns with the extant literature reporting MRI as the critical discriminator between pseudohypertrophy and other mimics, such as deep infiltrating intramuscular lipoma, which demonstrates fat-signal identical to subcutaneous fat with interdigitating fascicles, or diabetic myonecrosis, which produces diffuse edema without fatty replacement.3,6
Compartment syndrome is a feared cause of unilateral limb swelling and is often suspected in the setting of trauma due to rising pressure within a muscle compartment that may lead to eventual tissue ischemia and necrosis if left untreated. It may present with any of the classic six “p” clinical signs, which include pain, paresthesia, poikilothermia, pallor, paralysis, and pulselessness. While compartment syndrome must be on the differential diagnosis of painful, unilateral limb swelling, it was considered less likely due to the lack of classic history components, steadily improving pain level, and neurovascular integrity.
Lymphedema is a chronic edematous condition that occurs due to impaired lymphatic drainage. It is characterized by the accumulation of protein-rich lymphatic fluid in the interstitial space either through primary mechanisms, such as congenital abnormalities, or secondary ones, such as those caused by surgical complications, trauma, radiation, or infection. The resultant swelling is unilateral and occurs on the same side as the defective lymphatic source. It usually starts as soft and pitting, then progresses to firm and non-pitting in chronic stages due to fibrosis. The patient had two prior varicose vein surgeries in the affected left leg, dating 6–10 years ago. While a potential complication of varicose vein surgery is lymph node damage and subsequent impaired lymphatic drainage, the patient had no history of postoperative complications, and his presentation occurred years after the procedures. Moreover, his swelling was acute and painful, which would be unexpected in most cases of lymphedema, as it is most often a chronic process.
True muscle hypertrophy due to denervation is a rare but well-documented cause of unilateral limb enlargement. True muscle hypertrophy and pseudohypertrophy may originate from similar etiologies.8,9 True muscle hypertrophy, however, is thought to result from muscle denervation and subsequent compensatory hypertrophy of neighboring muscle fibers that remain innervated due to increased mechanical load. 12 MRI is useful to differentiate between the two diagnoses. In cases of true hypertrophy, signal intensities on MRI appear identical to normal muscle. 8 In contrast, in pseudohypertrophy, the enlarged muscle loses its signal intensity due to edema and adipose tissue infiltration. 12 Because the clinical presentation may be identical for both true muscle hypertrophy and pseudohypertrophy, MRI is critical for differentiation and ultimately confirmed the latter diagnosis in this case (Table 2).
Differential diagnosis of unilateral limb swelling considered in the described clinical case, with important clinical features, diagnostic methodology, and key distinguishing characteristics.
CBC: complete blood count; DVT: deep vein thrombosis; EMG: electromyography; MRI: magnetic resonance imaging; NCS: nerve conduction study.
Management considerations
Management of denervation pseudohypertrophy focuses on addressing the underlying cause and managing symptoms. In this case, optimizing diabetic control is crucial to prevent further progression of neuropathy. 6 Physical therapy, which was recommended but declined by the patient, can be beneficial in maintaining muscle function and preventing further complications.
Unique aspects of the case
This case is notable for its acute-onset presentation and self-limiting course. The bilateral involvement with marked left-sided predominance suggests a systemic process such as diabetic neuropathy with possible influence by local factors, potentially relating to the patient’s history of tibial fracture and vascular surgeries on the left leg. It is difficult to accurately postulate the possible mechanisms underlying the described clinical presentation due to the paucity of literature documenting acute presentations of denervation pseudohypertrophy. While the bilateral leg involvement points to a likely systemic etiology, such as diabetes, as previously mentioned, the presence of significant left leg predominance remains poorly understood. The patient’s orthopedic procedure in 1970 for repair of his left distal tibia was uncomplicated with no known injury to the lymphatic system. Moreover, he reported never experiencing any postoperative complications, repeat trauma to the region, or prior history of a similar presentation. His chronic venous insufficiency with two prior varicose vein surgeries of the affected left leg also raised questions about possible complications, particularly relating to lymphatic drainage. However, these procedures were performed 6–10 years ago with no postoperative history of unilateral leg swelling, pain, edema, or other concerning symptoms leading up to the current presentation.
Muscle pseudohypertrophy typically involves the replacement of atrophic muscle, as a result of denervation, with fatty infiltration as described above. Normally, a slow and chronic process, a rapid development may possibly point to an acute shift in fluid balance. A denervated muscle may have impaired autonomic function of capillary tone, lymphatic drainage, and interstitial fluid balance. Therefore, a local trigger, such as plausible acute venous congestion for this patient with long-standing venous insufficiency, could reasonably cause rapid enlargement due to impaired drainage. This may cause the appearance of acute enlargement secondary to edema from inappropriate fluid shifts.
The patient never underwent a previous MRI of his legs leading up to the described presentation, which would have shed light on whether pseudohypertrophy was present at baseline. However, it is reasonable to postulate that the patient’s long-standing diabetic neuropathy led to muscle denervation, particularly of his left medial gastrocnemius, and some level of subsequent pseudohypertrophy, which was likely present to some degree prior to the acute episode. A local inciting factor, as described above, such as acute venous congestion in the setting of chronic venous insufficiency of the left > right leg, could have disturbed the balance of interstitial fluid homeostasis due to the muscle’s insufficient nerve input, leading to the observed edema. This would explain the self-resolving clinical course and self-limiting nature of the patient’s symptoms. The edematous fluid was likely resorbed by the patient’s lymphatic system without complication, explaining his gradual clinical improvement.
Histopathological correlations
Although not performed in this case, a muscle biopsy in denervation pseudohypertrophy typically shows atrophy of skeletal muscle fibers with extensive infiltration by mature adipose tissue.6,8 This histological finding correlates well with the MRI appearance of fatty infiltration within the affected muscles.
Limitations and future directions
Long-term follow-up would be valuable to monitor the progression of the pseudohypertrophy and assess the effectiveness of conservative management. Additionally, EMG studies could provide further insights into the extent of denervation and help guide management. 6 Future research could focus on the potential relationship between denervation pseudohypertrophy and acute muscle injuries, as the connection between these conditions has not been well-established in the literature. Modern diabetic MRI research also suggests a role for quantitative fat-fraction markers and automated muscle segmentation tools to better characterize the progression of neuropathic muscle disease and potentially differentiate acute-on-chronic denervation patterns. 8
Conclusion
In conclusion, this case emphasizes the importance of considering denervation pseudohypertrophy in the differential diagnosis of unilateral limb swelling, particularly in patients with risk factors for neuropathy. 9 It also highlights the value of advanced imaging in reaching an accurate diagnosis in complex cases with overlapping clinical features.6,8,9
Footnotes
Ethical considerations
Our institution does not require ethical approval for reporting individual cases or case series.
Consent for publication
Written informed consent was obtained from the patient for their anonymized information to be published in this article.
Author contributions
Monica Botross: abstract, case summary, and discussion. Amirmohammad Shafiee: introduction, discussion, literature review, and references. Lisa Couch: initial treating clinician. Steven Schultz: radiologist. Stuart Pickell: supervising physician.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.