Introduction

One of the oldest recorded diseases in history is leprosy, a condition caused by a minuscule bacterium known as Mycobacterium leprae (M. leprae) and the more recently discovered M. lepromatosis. Also known as Hansen’s disease, leprosy is a bacterial infection that impacts the skin, limbs, nose, and upper respiratory tract. 

Once infected, the bacterium tends to establish itself in the skin and peripheral nerves, leading to skin lesions and sensory and motor loss in the face and limbs.^{1, 2}

Types of leprosy

Cases of leprosy are divided into three systems based on clinical features and immune response:^1,3

• Tuberculoid
• Lepromatous
• Borderline. 

Tuberculoid (TT)

In this situation, the host has strong cell-mediated immunity against the bacterium, exhibiting mild symptoms and only a few lesions.

Lepromatous (LLP)

Patients have a poor immune response, with the impact of the disease spreading to the skin, nerves, and other organs.

Borderline (BL)

Most patients have some extent of cell-mediated immunity, and the severity of their condition lies in the middle of the aforementioned types.

Peripheral nerves affected

Leprosy is a condition that preferentially impacts superficially located nerves, such as the facial, ulnar, median, radial, peroneal (fibular), and posterior tibial. This arises due to the propensity of M. leprae to proliferate in cooler peripheral locations. 

Damage to these nerves leads to symptoms such as numbness, muscle weakness, and deformities in the hands, feet, and face.^{3, 4}

Pathogen invasion mechanisms

The various routes of entry for M. leprae into the peripheral nerves include direct access to the terminal cutaneous nerves (small nerve endings at the skin) or through our nasal pathways and into the bloodstream. 

Once the bacterium has entered our body, it binds itself to exposed Schwann cells and generates an immune response. Schwann cells myelinate peripheral neurones in the peripheral nervous system, which forms an insulating layer that protects and supports the area around nerves.⁵ 

M. leprae uses specific surface-exposed antigens to adhere to and penetrate peripheral nerves. The surface proteins LBP21 & PGL-1 bind to laminin-2 (myelinating factor) receptors and facilitate penetration into Schwann cells.  M. leprae replicates very slowly inside host cells, requiring 12-14 days to complete an entire generation, and can survive up to 46 days in humans. 

Infected Schwann cells are manipulated into producing insulin-like growth factors, which upregulate glucose uptake and enable the bacteria to survive for extended periods inside host cells. Moreover, Schwann cells may be reprogrammed into stem cells capable of proliferating and migrating to other parts of the body. This process also stimulates immune-related genes within Schwann cells, thereby priming the area for subsequent inflammation and immune-mediated nerve damage.^{2, 3, 6}

Direct mechanisms of damage 

Before the host immune system responds, M. leprae disrupts the function of Schwann cells and leads to damage of peripheral nerves through: ^{6, 7}

• Dedifferentiation: M.leprae activates signalling pathways that cause Schwann cells to dedifferentiate. As a result, the cells lose their normal identity and stop supporting the nerve cells
• Release of damaging molecules: infected Schwann cells produce inflammatory molecules and matrix-degrading enzymes that disrupt the nerve structure, thus making the area more susceptible to inflammation and further immune attacks

Indirect mechanisms of damage 

Cell-mediated immune responses 

After M. leprae enters Schwann cells, the antigens present on the bacterium are processed and presented on the surface of infected cells. This signals to T cells (key immune cells) and alerts the immune system to initiate an attack on the infected cells. 

Depending on the type of leprosy, there are two different cell-mediated immune responses that may follow: 

• Tuberculoid 
• Lepromatous

Tuberculoid

The immune system launches a strong immune response by deploying Th1 cells. Th1 cells are a subtype of helper T cells that release cytokines to coordinate an immune response. These cells activate macrophages, which aim to destroy the bacteria before they spread. 

However, immune cells (mainly macrophages) may cluster together and form granulomas that surround and trap the infection. This leads to nerve inflammation, which can damage and scar nerves. 

Lepromatous

There is a weak immune response, allowing the bacteria to proliferate freely inside Schwann cells and their resident macrophages. As a result, there is no damage from early inflammation; however, the bacterial load is allowed to increase, leading to widespread nerve damage. 

Type 1 & type 2 reactions

Patients with leprosy also experience severe immune flare-ups that result in sudden and serious inflammation, especially of nerves.

Type 1

Most commonly seen in borderline forms of leprosy, a type 1 reaction is triggered by shifts in immunity. 

This results in the following symptoms:

• T cells and macrophages become hyperactivated
• Pre-existing skin and nerve lesions are further inflamed 
• Nerve swelling occurs rapidly and may result in permanent nerve damage 

Type 2

Also known as erythema nodosum leprosum (ENL), it is a systemic reaction most commonly seen in lepromatous leprosy. 

This reaction is driven by antibodies and leads to: 

• Antibodies will bind to M.leprae antigens and form immune complexes
• Immune complexes will activate white blood cells and cause widespread tissue inflammation 
• Patients will experience fever, joint pain, painful skin nodules, and acute nerve inflammation 

These immune flare-ups can happen during or after leprosy treatment, with urgent care needed to prevent permanent nerve damage.^{2, 3}

Schwann cell activation

Schwann cells are not only the victims of infection, but they can also actively contribute to worsening nerve damage. Schwan cells express toll-like receptors (TLRs) that recognise components of the bacterial cell wall. 

Activation of these receptors by M.leprae, specifically TLR2, induces the death of Schwann cells and releases inflammatory cytokines (inflammatory factors) that prime the area for further immune-mediated damage.³

Consequences of nerve damage 

Nerve damage can lead to an array of physical, sensory, and functional impairments that may cause permanent complications in patients. 

Sensory deficits

Skin lesions form as a result of inflammation, which results in decreased sensation to touch, temperature, or pain. These affected areas are prone to injuries, burns, and repeated trauma, which go unnoticed due to the numbness. Moreover, nerve damage produces loss of sweating and dryness in the hands and feet, which significantly increases the risk of ulceration.^{1, 3}

Motor weakness

Sensory nerve damage that results in numbness can cause repeated injuries and subsequent loss of limbs. Additionally, the accompanying damage to motor nerves leads to major problems in producing basic hand movements, leading to issues in performing daily activities. 

This can further lead to secondary disuse muscle atrophy, where patients lose muscle mass due to disuse, thus creating further impairments in their motor capabilities. ⁶

Chronic pain

Despite the loss of sensation as a result of leprosy, neuropathic pain is still a common symptom experienced by patients. The pain, a burning sensation caused by the nerve injury, can persist and develop several years after treatment of the disease.²

Social & psychological impact

Nerve damage often leads to visible deformities, functional limitations, and even long-term disabilities in some patients. Patients who have been disfigured may experience discrimination and low self-esteem, leading to depression and a reduced quality of life. Moreover, long-term disability among people affected by leprosy may burden patients with reduced independence, thereby further reinforcing their emotional distress.²

Treatment & management 

Effective treatment and management of leprosy involves anti-inflammatory and anti-bacterial treatments, reconstructive surgeries, physiotherapy and preventative care. 

Anti-bacterial treatment

The gold standard for targeting M. leprae is a combined regimen of antibiotics coined the Multidrug Therapy (MDT). 

MDT, which includes rifampicin, dapsone, and clofazimine, aims to effectively kill M. leprae and halt its transmission. The treatment usually lasts 6-12 months and reduces the risk of future nerve damage, but does not correct existing nerve injury.²

Managing inflammation

In order to reduce the immune response, corticosteroids play a vital role as an anti-inflammatory therapy, helping to reduce the inflammation. By reducing inflammation, the treatment can prevent permanent nerve damage and relieve symptoms.^{2, 3}

Supportive care

Physiotherapy is crucial to maintaining muscle strength, maintaining mobility, and helping patients adjust to daily activities. Patients may also need mental health support to address the emotional distress and social challenges associated with leprosy and its complications.²

Prevention and diagnostics 

Leprosy vaccine

While vaccine development has been limited due to leprosy’s long incubation period, recent advancements have presented us with LepVax, a subunit vaccine composed of M. leprae-specific antigens. 

In experimental studies, LepVax reduced bacterial load in mice and also delayed nerve damage when administered after infection. This offers new hope for post-exposure prevention and highlights the potential of reducing transmission before damage occurs.²

Diagnostics 

Accurate diagnosis of leprosy is crucial for early intervention. 

The World Health Organisation (WHO) defines a case of leprosy as an individual who presents one of the following symptoms:

• Definite loss of sensation in a pale or reddish skin patch 
• Enlarged or thickened peripheral nerve with loss of sensation and/or weakness in muscles supplied by the nerve
• Presence of acid-fast bacilli in a slit-skin smear

Moreover, by performing routine nerve function assessments, clinicians can achieve early diagnosis, effectively monitor treatment response, and evaluate nerve recovery over time.²

Conclusion 

Leprosy remains a serious condition with the potential for severe and permanent complications. However, the overall outlook improves if your doctor diagnoses the disease to stop the spread of the disease and prevent long-term disability. 

Even if permanent medical complications occur, recent advancements in therapeutic measures have provided ways of potentially reversing nerve damage, managing inflammation, and improving a patient’s overall quality of life.