Venous thromboembolism (VTE) is a well-established cause of morbidity and mortality in the adult population [1]. The risk of VTE is known to increase with age and prolonged immobilization, amongst other risk factors [1]. Neurologic diseases that cause lower limb immobility are known to have an increased risk of VTE [2]. VTE is a known complication of motor neuron diseases like amyotrophic lateral sclerosis, but the studies evaluating its incidence have had low sample sizes. We aimed to further delineate the incidence of VTE in our population of patients with motor neuron diseases, and to determine whether this risk is different among the various MND subtypes.

We retrospectively reviewed patients with a diagnosis of ALS, primary lateral sclerosis (PLS), or other motor neuron disease at our institution between 2017 and 2021. Patients were excluded if they were under 18 years old and if they had not been formally evaluated by the institution’s ALS multidisciplinary clinic. The medical record was queried to determine if the patient has had a VTE event, including pulmonary embolism, deep venous thrombosis, or both. Progress notes, imaging studies, medications, and problem lists were evaluated.

A total of 650 patient records were identified from the query. 109 patients either did not have a clear diagnosis of MND or had an incorrect diagnosis. Of 541 patients with MND, 88.9% had ALS, 2.4% had PLS, and 8.7% had other MND (Table 1). The median age was 65.3 years (57.4 - 72.6 IQR), and 56.4% identified as male. The median BMI was 23.4 (20.4 - 26.6 IQR).

Table 1: Demographic Comparisons between Patients with VTE.

A total of 52 patients had a history of VTE, for a total incidence of 9.6%.  Of these patients, 76.9% had DVT only, while 7.7% had a PE only? 15.4% of patients had both DVT and PE.

Univariate logistic regression demonstrated that age was non-significantly associated with VTE (OR 1.02, 95% CI 1.00 - 1.05, p=0.10). BMI was not significantly associated with VTE (p=0.11), and neither was gender (p=0.21). Race or ethnicity was not significantly associated with developing VTE. An ANOVA analysis comparing different MND subtypes showed a statistically significant difference in VTE rates (9.2% in ALS; 30.8% in PLS; 8.5% in other MND; p=0.032). In a multivariate logistic regression after adjusting for age and gender, having ALS was associated with 75% lower odds of having a VTE compared to patients with PLS (OR 0.25, 95% CI 0.07 - 0.86, p=0.03).

After a 5-year review of patients with MND seen at a high-volume center, we found a VTE incidence of 9.6%, with a statistically higher rate of VTE in patients with PLS. Notably, this incidence is higher than the VTE risk in the general population [1]. While rare in younger individuals, the incidence of VTE increases to about 1% per year in the elderly [3].

It is expected that patient’s with MND have a higher risk of VTE, given the debility that these conditions can cause [4]. A meta-analysis evaluating the risk of venous thromboembolism among patients with lower leg immobility measured the risk close to 17.1% [5]. The AT-AGE study evaluating the risk of VTE in the elderly found that even transient immobility was associated with a five-time higher odds of developing thrombosis [6].

The risk of VTE in ALS has been noted previously, but the results have been variable. Elman et al. found a VTE prevalence of 2.97% in their ALS population, and found that immobility was associated with a 5 times higher risk of VTE compared to those that are not immobile [7]. Padilla et al, also performed a retrospective study in which they found a 3.9% prevalence of VTE, and found an association with continuous non-invasive ventilation, obesity, and the presence of high blood pressure [8]. Two prospective studies have noted even higher risk in patients with ALS, though are limited by sample size. Gladman et al. found that the annual incidence of VTE in their cohort of ALS patients was 11.2% [2]. Similarly, a quasi-experimental study performed by Caballero-eraso et al. found that the incidence of VTE was 13.6% in their population [9]. Though our study is retrospective, it does harness the sample size available at a large ALS center.

We hypothesize that our reported VTE incidence likely represents an underreporting for several reasons. First, leg pain and swelling are common symptoms in patients with MND, and may not always be recognized as VTE by providers [10]. Second, respiratory symptoms related to pulmonary emboli may also be seen as respiratory symptoms from diaphragmatic dysfunction and may not always be recognized [11]. Next, towards the late stages of disease, ALS patients are not seen in clinic as frequently, and fewer diagnostic tests are performed at the late stages of disease [12]. Lastly, if a patient with MND had a terminal event related to a VTE, we also would not be able to capture this data. There is some evidence that the VTE risk in ALS is likely underreported. For instance, in an autopsy study performed in 2009, autopsies performed on 100 patients that deteriorated due to their clinical condition found that pulmonary embolism represented 6% of death, and was primarily found in ALS patients with spinal onset disease [13].

A novel finding in our study is that the risk of VTE appears higher among the subset of patients with PLS. This is an interesting finding given that PLS typically have a slower disease course and is typically associated with less debility [14,15]. Larger studies with patients with PLS are needed to confirm this finding.

This study raises the question about whether or not patients with MND, and in particular those with lower leg immobility, would benefit from VTE prophylaxis. In the prospective study performed by Gladman et al., they found that patients with leg onset ALS or significant leg weakness had a VTE incidence rate that was 3 times higher than those without leg weakness [2]. The risk of VTE was shown to be reduced by 32% with low molecular weight prophylaxis among patients with lower leg immobility, but it is unclear whether these results can be generalized to the MND population [5]. In addition, up to 30% of patients with VTE will have recurrence in 10 years, and neurologic disease with leg paresis is a risk factor for recurrence [1,16].

While prophylaxis most certainly involves a discussion of risks and benefits, another option is to screen patients with compressive ultrasonography during routine visits. Caballero-Eraso used this methodology to evaluate patients with VTE, and found that 50% of the patients that were found to have VTE were completely asymptomatic [9].

Future studies should try to identify MND patients deemed to be at higher risk for the development of VTE, including ambulatory status, neurologic disease severity, and pulmonary status. Identifying high-risk patients may lead to earlier detection of VTE and improve quality of life.

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