To Determine the Efficacy of Pentoxifylline in the Management of Bell’s Palsy

Abstract

Background and aims

Bell’s palsy is an acute, unilateral, lower motor neuron peripheral facial paralysis. It is the most common cause of facial paralysis in the ages ranging from 13 to 65 years. It not only causes physical disfigurement of face but is also associated with social stigma and psychological trauma to the patient. In Bell’s Palsy, there is hypoxic damage to the nerve due to reduced blood flow and cellular injury to the capillaries. Pentoxifylline is a phosphodiesterase inhibitor that increases the cAMP and cGMP levels at the site of the RBC cell membrane thereby improving the dexterity of the cell membrane allowing the RBCs to pass through the damaged and narrowed blood vessels thereby improving the perfusion and oxygen delivery to the damaged tissues. Vasoactive agents are not routinely used as an active component in the treatment. Since vascular compromise plays a predominant role in the pathophysiology of Bell’s palsy, it is proposed that the addition of a vasoactive agent like Pentoxifylline can improve the recovery rate and shorten the duration of treatment in the management of Bell’s Palsy.

Materials and methods

The study was conducted in the Department of ENT, BMCRI, Bangalore during the period February 2021 to August 2022. This is a prospective randomized control study which included 70 patients attending the out-patient department of ENT, Bangalore Medical College and Research Institute, Bangalore. Written informed consent was taken from all patients included in the study. A detailed history, thorough clinical examination, and relevant investigations were done for these patients. Patients were randomly divided into Group A and Group B based on random numbers generated by the WINPEPI software version 11.65. The study group (Group A) received standard treatment in addition to Tab Pentoxifylline 400 mg TID for 1 week. The control group (Group B) received only the standard treatment regimen. Patients were followed up on Days 5, 10, 15, and 6 months to assess recovery following treatment. The recovery of facial nerve function was evaluated as per the House-Brackmann Grading system for any improvement. Both pre-treatment and post-treatment HB grades were analyzed. The data collected were tabulated and subjected to statistical analysis using ANOVA.

Results

The age distribution of the patients showed that the most common age group affected in this study was 18–30 years. Males were affected more than females (1.2:1). The most common HB grade at presentation noted in this study was Grade 4 in both groups (54.2%). At the beginning of the treatment, in Group A, around 43% patients had HB grade of 3 and 57% patients had HB grade of 4. In Group B, around 20% patients had HB grade 2, 28.57% patients with grade 3 and 51.43% patients with grade 4. After a follow-up period of 6 months, in Group A, around 43% of patients achieved a HB grade of 1, 51% patients achieved a grade of 2 and about 6% patients had a grade of 3. In Group B after a follow up period of 6 months, 29% patients achieved HB grade of 1, 46% patients achieved grade of 2 and 26% patients had a grade of 3. It was observed that 42.86% of patients had better outcomes (Normal facial function) in Group A (Study group) compared to 28.57% of patients in Group B (Control group). It is evident that a patient who presented with HB grades of 2 or 3 and who presented within 5 days had better chances of recovery which was statistically significant (p = 0.001).

Interpretation and conclusion

From the present study, it may be concluded that Bell’s palsy occurs in all age groups. It affects younger age groups more commonly (2nd decade) and affects males more than females. The study group who had received Tab Pentoxifylline along with standard treatment had better outcome. This highlights the benefit of vasoactive agent in the management of Bell’s palsy by improving the oxygen delivery to the affected tissues.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12070-023-04298-9.

Introduction

Bell’s palsy (BP), also known as Spontaneous Idiopathic Facial Paralysis, is a sudden, unilateral, lower motor neuron peripheral facial paralysis named after the Scottish anatomist Sir Charles Bell. [1] It is the most common cause of facial paralysis in the ages ranging from 13 to 65 years. [2] It not only causes physical disfigurement but is also associated with social stigma and psychological trauma to the patient. It is idiopathic as no cause has been known and is a diagnosis of exclusion. Globally, about 20–30 cases of Bell’s Palsy are reported per 100,000 population yearly [2] affecting 1 in 65 people in their lifetime. [3] There is no gender predisposition although it is common during the 3rd trimester of pregnancy. [3] Both sides of the face are equally affected.

The facial nerve, which is the seventh cranial nerve, has motor, sensory, special sensory, and autonomic/visceral components. The nerve has the most intricate routes compared to other cranial nerves as it runs intracranially, intratemporally, and extratemporally. It emerges from the stylomastoid foramina giving rise to the terminal branches supplying the face and the cervical region.

The motor nucleus of the nerve supplies the muscles of facial expression, auricular muscles, the posterior belly of the digastric, stapedius muscle, and stylohyoid muscle. The sensory nucleus, located posterolateral to the motor nucleus, receives taste information from the palate, the floor of the mouth, and the anterior two-thirds of the tongue. The parasympathetic system supplies the sublingual, submandibular, palatal, and nasal salivary glands from the superior salivatory and lacrimal nuclei.

Bell’s palsy typically results in a partial or total inability of the affected side’s facial mobility. Even though it recovers on its own, BP can cause facial paresis or paralysis, which can result in severe transient oral insufficiency and the inability to close one’s eyes, which can cause chronic eye damage. Moderate to severe facial asymmetry may persist in about 25% of BP patients, significantly lowering patients’ quality of life. [3].

Despite the debilitating effects, the exact aetiology of BP is not known. It is a diagnosis of exclusion. One of the theories states that there is hypoxic damage to the nerve due to reduced blood flow and cellular injury to the capillaries. Pentoxifylline is a phosphodiesterase inhibitor that increases the cAMP and cGMP levels at the site of the RBC cell membrane thereby improving the dexterity of the cell membrane allowing the RBCs to pass through the damaged and narrowed blood vessel and improving the perfusion and oxygen delivery to the damaged tissues. [4].

The standard treatment used in Bell’s palsy is a combination of a corticosteroid and antiviral agent. [5] Vasoactive agents are not routinely used as an active component in the treatment. Since vascular compromise plays a predominant role in the pathophysiology of Bell’s Palsy, it is proposed that the addition of a vasoactive agent like Pentoxifylline can improve the recovery rate and shorten the duration of treatment in the management of Bell’s Palsy.

The objectives of the Study include -.

1. To assess the recovery of Bell’s Palsy in the study group.

2. To assess the recovery of Bell’s Palsy in the control group.

3. To determine the efficacy of Pentoxifylline by comparing the recovery of Bell’s Palsy between the study and control groups.

Methods

The present study titled “TO DETERMINE THE EFFICACY OF PENTOXIFYLLINE IN THE MANAGEMENT OF BELL’S PALSY” was undertaken in the Department of ENT, BMCRI, Bangalore, Karnataka. It was a Prospective Randomized Controlled Study done within the period from February 2021 to August 2022. A total of 70 patients presenting with Bell’s Palsy were included in the study.

Inclusion Criteria

1. Patients between the age group of 18–65 years who are willing to give informed written consent.

2. Patients who fall under the diagnostic criteria of Bell’s Palsy [5].

   1. Absence of central nervous system disease including strokes.
   2. Paralysis of muscles of one side of the face.
   3. Absence of signs of the ear such as ear discharge/vertigo/earache.
   4. Absence of cerebellopontine angle disorders.

3. No known aetiology causing the palsy.

Exclusion Criteria: [5]

1. Connective tissue disorders.

2. History of iatrogenic causes that might have contributed to the palsy such as surgeries.

3. Patients having contraindications to Pentoxifylline such as:

   1. Renal and liver disorders such as cirrhosis.
   2. Bleeding disorder or those who are at higher risk of bleeding and those who are under anticoagulants.
   3. Severe coronary artery disease including myocardial infarction.

Data Collection

In this study, 70 patients arriving at the OPD diagnosed with Bell’s Palsy were included. Informed written consent was taken. A detailed history followed by a complete general physical examination and a complete otorhinolaryngological examination was done. The patients underwent audiological tests like the Tuning Fork test and Impedance audiometry including stapedial reflex. Other causes of facial nerve palsy were ruled out based on history and clinical examination.

The standard treatment regimen included the following: [6, 7].

1. Steroid – Tab Prednisolone 1 mg/kg body weight TID for 5 days after food. Based on the response, the medication will be tapered in another subsequent 10 days. Total duration of steroids given was for 15 days.

2. Antiviral – Tab Acyclovir 800 mg 5 times a day for 10 days.

3. Capsule Pantoprazole (40 mg) with Domperidone (30 mg) once a day before food for 10 days.

4. Hydroxymethyl cellulose drops for protection of the eyes.

5. Dose of vitamin B12 1500 micrograms orally per day [8].

6. Facial physiotherapy.

Patients were randomly divided into Group A and Group B based on random numbers generated by the WINPEPI software version 11.65 and the patients were asked to pick up a paper bearing numbers from 1 to 70 which determined the treatment group they would belong to. The study group (Group A) received, in addition to the standard treatment, Tab Pentoxifylline 400 mg TID for 1 week. The control group (Group B) received the standard treatment regimen. The follow-up of the patient was done on the 5th day to taper the steroid dose. If no improvement was seen on the 5th day, the same steroid dose was continued for 5 more days (till day 10) and then on the 10th day, the dose was tapered. Further, follow-up was done on the 15th day and at the end of 6 months by assessing of facial nerve functions. Facial nerve function was evaluated using HB grading system at the beginning and at subsequent follow-ups and the results were tabulated.

Sample Size Estimation

Based on the previous study conducted by Kinishi et al [9] and SG Mahesh et al [10], by considering the proportion of patients who recovered from Bell’s Palsy after taking an oral steroid combination (68%) concerning the proportion of patients who recovered from Bell’s Palsy after taking steroid-dextran-pentoxifylline therapy (94%) respectively, the sample size was calculated as 70. A minimum of 35 patients with Bell’s Palsy were included in each group.

Results

The results and analysis of this study are as follows.

1. Age Distribution

Table 1 shows the age distribution of the present study. In our study, the range of age of the patients varied from 18 to 65 years. Incidence of Bell’s Palsy was more commonly noticed among the age groups of 18–30 years (48.57%) with equal numbers in both groups. The least number of cases were noted in the ages above 50 years of age (5.7%) concluding that in the present study, Bell’s palsy was common among the younger age groups. (Not statistically significant, P = 0.57).

Table 1.

Age distribution of study subjects

YEARS	GROUP A	GROUP B
18–30	17	17
31–50	15	17
> 50	3	1

2. Sex Distribution

As shown in Table 2, out of 70 patients, 38 were males (54.3%) and 32 were females (45.7%) concluding that in the current study, it was more commonly observed in the males (1.2:1) but it was not statistically significant (p = 0.631).

Table 2.

Sex distribution of study subjects

Gender	Group A	Group B	Total Study Subjects
Male	20	18	38
Female	15	17	32

3. House- Brackmann Grading Distribution

In this study, the most common grade at presentation was grade 4 in both groups (54.2%). At the beginning of the treatment, in Group A, around 43% patients had HB grade of 3 and 57% patients had HB grade of 4. In Group B, around 20% patients had HB grade 2, 28.57% patients with grade 3 and 51.43% patients with grade 4. After a follow-up period of 6 months, in Group A, around 43% of patients achieved a HB grade of 1, 51% patients achieved a grade of 2 and about 6% patients had a grade of 3. In Group B, after 6 months, 29% patients achieved HB grade of 1, 46% patients achieved grade of 2 and 26% patients had a grade of 3.

4. Comparison of HB Grades from Baseline to 6 Months

In Tables 3 and 4 above, HB grades are shown and compared between groups A and B from baseline (Start of the treatment up to 6 months). At the beginning of the treatment, 57% of patients in Group A and 51% of patients in Group B had HB grade 4. After 6 months of follow-up, around 43% of patients in group A and 28.5% of patients in Group B achieved an HB grade of 1 which is normal facial nerve function. None of the patients in both groups had HB grades of 4, 5, or 6 after 6 months of follow-up. Only 5.7% of patients in Group A and 25.71% of patients in Group B had an HB grade of 3 after 6 months. (Results were significant at the start of the treatment, on days 5 and 15; P = 0.017, 0.029, and 0.001 respectively).

Table 3.

Change of HB grade from baseline to 6 months for both groups

Descriptive		CHANGE OF HB GRADE FROM BASE LINE TO SIX MONTHS FOR GROUP B
		Base line HB Grade n (%)	Day 5 n (%)	Day 10 n (%)	Day 15 n (%)	At 6 months n (%)
Base line HB Grade	1	0 (0.00)	0 (0.00)	(0.00)	6 (17.14)	10 (28.57)
	2	7 (20.00)	7 (20.00)	7 (20.00)	5 (14.29)	16 (45.71)
	3	10 (28.57)	10 (28.57)	10 (28.57)	20 (57.14)	9 (25.71)
	4	18 (51.43)	18 (51.43)	18 (51.43)	4 (11.43)	0 (0.00)
	5	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)
	Total	35	35	35	35	35

Table 4.

Change of HB grade from baseline to 6 months for both groups

Descriptive		CHANGE OF HB GRADE FROM BASE LINE TO SIX MONTHS FOR GROUP A
		Base line HB Grade n (%)	Day 5 n (%)	Day 10 n (%)	Day 15 n (%)	AFTER 6 months n (%)
Base line HB Grade	1	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	15 (42.86)
	2	0 (0.00)	0 (0.00)	7 (20.00)	19 (54.29)	18 (51.43)
	3	15 (42.86)	15 (42.86)	16 (45.71)	14 (40.00)	2 (5.71)
	4	20 (57.14)	19 (54.29)	11 (31.43)	2 (5.71)	0 (0.00)
	5	0 (0.00)	1 (2.86)	1 (2.86)	0 (0.00)	0 (0.00)
	Total	35	35	35	35	35

For Group A, 57.14% of patients had Grade 4 palsy at the beginning of the treatment. After 6 months of follow-up, almost all patients but 2 achieved HB grades of below 3 (42.86% of patients achieved an HB grade of 1 which is normal function, and 51.43% of patients achieved an HB grade of 2).

For Group B, 51.43% of patients had Grade 4 palsy at the start of the treatment. After 6 months of follow-up, 26 patients achieved HB grades of below 3. (28.57% of patients achieved an HB grade of 1, and 45.71% of patients achieved an HB grade of 2).

5. Correlation and Strenghth of Association

It was evident that the lower HB grades of 2 and 3 have better chances of complete recovery which was statistically significant. (p = 0.001) (Correlation coefficient value of 1 at 6 months). It was observed that 42.86% of patients had better outcomes (Normal facial function) in Group A (Study group) compared to 28.57% of patients in Group B (Control group) which was statistically significant during the time interval of 6 months (p = 0.038; p < 0.05).

Discussion

Bell’s Palsy (BP) is also known as Idiopathic Facial nerve paralysis is an acute and sudden unilateral lower motor neuron paralysis which primarily affects the muscles of facial expression and is associated with significant social and psychological stigma to the patient. There are many theories proposed regarding its pathophysiology since no known cause has been found and hence it is a diagnosis of exclusion. Most common pathophysiological mechanism that has been accepted is hypoxic damage to the nerve due to decreased blood flow and cellular injury to the capillaries. Other mechanisms proposed include oedema and inflammation of the nerve due to ischemia leading to hypoxia and viral aetiology especially varicella zoster virus reactivation. The standardized treatment which has been proposed and has been found to achieve almost complete recovery with low rates of sequelae are Steroid such as Prednisolone and antiviral drugs such as Acyclovir. Other supportive measures which may hasten recovery and reduce further sequelae include Hydroxy methylcellulose eye drops, hyperbaric oxygen, oral vitamin B12 and facial physiotherapy. Along with this standard treatment, it has been proposed that addition of vasoactive agents like Pentoxifylline can improve the RBC dexterity allowing them to pass through the damaged blood vessels thereby restoring the blood supply and oxygen delivery to the neighbouring tissues and allowing early recovery of the damaged nerve.

The current study was conducted on 70 patients who presented in our department with BP. 35 patients received standard treatment and 35 received standard treatment along with oral Pentoxifylline.

Age and Gender Distribution

In our study, Bell’s Palsy was observed more commonly in the age group of 18–30 years with the mean age of 33 years which was similar to a study conducted by SG Mahesh et al. [10] in 2012 which included 26 patients and the mean age was 32. The male to female ratio in our study was 1.2:1 which is almost similar to that of the above-mentioned study where the ratio was 1.5:1.

38 out of 70 patients in our study were males (54.3%) and 32 (45.7%) were females which is in contrast to the study conducted by Peitersen E et al. [11] where out of 1,701 cases of Bell’s palsy, 818 of the patients (48.1%) were male and 883 (51.9%) were females.

Etiopathogenesis

A meta-analysis conducted by Quant et al. [12] to ascertain whether antivirals in combination with steroids given to Bell’s palsy patients had a greater degree of facial muscle improvement than steroids alone detailed that the most common aetiopathogenesis is the neuronal inflammation associated with palsy and is thought to be secondary to viral infection. Herpes simplex virus has been detected in the endoneurial fluid in patients with palsy. Based on this evidence, some clinicians treat patients with antivirals, including acyclovir, famciclovir, and valaciclovir.

In a study conducted by M Kinishi et al. [9], 231 patients with Bell’s Palsy were included and evaluated for recovery for 6 months. According to this study, Bell’s palsy results in oedema and primary or secondary ischemia of the facial nerve, leading to nerve compression and hypoxia.

An article published by Dhruvashree S et al. [13] details the management of Bell’s Palsy. According to this article, ischemia of the facial nerve is associated with vascular distension, inflammation, and oedema in post-mortem Bell’s palsy cases.

According to our study, it is proposed that vascular compromise plays a predominant role in the pathophysiology of BP. Hence, adding Pentoxifylline to the standard treatment regimen can improve the recovery rate.

Standard Treatment for Bell’s Palsy

An article published by Dhruvashree S et al. [13] details the management of Bell’s Palsy. According to the said article, when steroids are started within 72 h after the onset of symptoms, the maximum benefit is observed. Although there is no ideal treatment plan, 50–60 mg of prednisolone per day for 10 days has been used frequently in adults. Prednisolone has been administered up to 80 mg at a dose of 1 mg/kg per day. In diabetic patients, doses greater than 120 mg/day have been used without issue. The antiviral medications used in the studies were valaciclovir (1000 mg/day for five days) or acyclovir (400 mg five times day for five days).

In a study conducted by Khajeh A et al. [14] a randomized control trial conducted on 43 Children (2–18 years old) with Bell’s palsy. Prednisolone (2 mg/kg/day) was administered to the first group of 23 patients, while the remaining patients received a combination of prednisolone and acyclovir (a combination of 2 mg/kg/day prednisolone and 10 mg/kg acyclovir every 8 h for 7 days). In groups I and II, the rates of full recovery were respectively 65.2% and 90% (p = 0.04). The findings of this study demonstrated that prednisolone and acyclovir medication is significantly more effective than prednisolone therapy alone in treating Bell’s palsy patients.

In a systematic review and meta-analysis conducted by John R. de Almeida et al. [15] they estimated the link between antiviral drugs and corticosteroids and the likelihood of people with Bell palsy experiencing a less-than-satisfactory facial recovery. There were 2786 eligible patients. Corticosteroids were linked to a better benefit when paired with antiviral medicines (P = 0.004) than when used alone. Antiviral medicines were linked to a greater risk reduction when taken with corticosteroids than when used alone (P = 0.05).

In the study by Kang HM, Jung SY, et al. [16] they compared the effectiveness of a steroid combined with an antiviral drug (S + A group) to a steroid only group (S group) in helping Bell’s palsy patients recover. In total, 1342 Bell’s palsy individuals were included in this study. Prednisolone plus antiviral medications were used to treat patients in the S + A group (n = 569) and prednisolone alone was used to treat patients in the S group (n = 773). With initially severe Bell’s palsy (HB grades V and VI), the rate of recovery for HB grades I and II was greater in the S + A group than in the S group (P = 0.001). The rates of recovery, however, were comparable to mild to severe palsy (HB grades II–IV) in the beginning (P = 0.502).

Based on the above-mentioned studies, our study included combination of Prednisolone and Acyclovir as the standard treatment regimen for both the groups.

Clinical Evaluation for Bell’s Palsy

In a study conducted by Khajeh A et al. [14] using an information based on the House-Brackmann Scale, they assigned grades for facial nerve paralysis and the necessary data were retrieved.

In a prospective randomized controlled study conducted by Thomas Berg et al. [17] where the facial function at 12 months was assessed with House-Brackmann grading systems and outcome was evaluated.

A study conducted by Yoo MC et al. [17], where they studied the causes of enhanced facial nerve function with BP treatment function was initially assessed by HB grading in 1364 patients with BP. According to this, it is widely accepted system for grading facial function.

In our study, the outcome of the treatment was evaluated according to the HB grading system based on the above-mentioned studies.

Addition of Pentoxifylline

In our study, oral Pentoxifylline 400 mg TID was added to the standard treatment regimen for the study group based on the studies mentioned below.

In the study by Stennert E [18], 150 patients with Bell’s Palsy were treated with a combination of Dextran, Pentoxifylline, and Cortisone (Stennert’s protocol). After 10-day treatment, only 32 patients (24%) still suffered from clinically complete paresis. This study showed that during therapy there was a change from clinically complete to incomplete paresis in 54% of the patients.

In a study conducted by SG Mahesh et al. [10] which included 26 patients, 19 patients suffered from Bell’s Palsy who were treated with Modified Stennert’s Protocol which included Dextran, Pentoxifylline, Hydrocortisone and Acyclovir. It was observed that this protocol showed significant symptomatic improvement and had a success rate of 94% for patients with BP.

In a study conducted by M Kinishi et al. [9], 231 patients with Bell’s Palsy were included and evaluated for recovery for 6 months. One group was given Steroid only therapy and another group was treated with steroid-Pentoxifylline-Dextran therapy (SD). It was observed that all patients with incomplete palsy (Score > 20 according to Hosomi’s method modified from that of May [19]) recovered completely regardless of the treatment. Of the 111 patients given SD therapy, 97 (87%) recovered completely, and 14 (13%) partially. Of the 37 patients treated with oral steroids, 25 patients (68%) recovered completely and 12 (32.4%) partially which was statistically significant (P < 0.05). Based on this study, oral steroids are best used in cases of incomplete palsy unless a complete palsy develops. In these latter cases, SD therapy should be started immediately.

A study conducted by Sittel C et al. [20], included 334 patients suffering from BP. 239 patients were treated with prednisone, dextran, and pentoxifylline. Patients with incomplete palsy obtained a full recovery in 98% of cases compared to 94% without treatment in this study. Patients with complete paralysis regained normal function in 77% of cases, as opposed to 61% of patients in this study.

Key Message

Bell’s palsy is a sudden, acute facial nerve paralysis of unknown origin and has been associated with a significant social and psychological stigma that requires immediate treatment. The most common age group affected by the palsy is 1st and 2nd decade. There is no gender predilection for BP. According to our study, the presence of co-morbidities did not affect the outcome of the treatment. The House-Brackman grading system is the most common grading scale along with other supplementary tests such as electroneuronography which has been used to define the severity and outcome of facial palsy/paralysis. Pentoxifylline is a xanthine derivative and a phosphodiesterase inhibitor that has been approved for use in peripheral vascular disease as a vasodilator. It prevents vascular spasm by improving red cell deformability (hemorheological effect), reduces blood viscosity, and decreases platelet aggregation. Since it has been postulated that vascular spasm is one of the etiopathological mechanisms explaining the occurrence of Bell’s palsy, addition of Pentoxifylline has been shown to be effective in its recovery. In our study for HB grades of 2 and 3, adding Pentoxifylline in the standard treatment regimen had better outcome of recovery and was statistically significant. Hence, addition of Pentoxifylline in the standard treatment regimen as a vasoactive agent can improve the blood supply and oxygen delivery to the tissues thereby leading to better chances of recovery.

Electronic Supplementary Material

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Declarations

Conflict of interest -

The authors declare that they have no conflict of interest.

Research Involving Human Participants and/or Animals

– Yes, Human participants.

Informed Consent

Informed Written Consent was taken.