Apr 15, 2024 | Patent
When navigating the world of patents and patentable inventions, we come across essential requirements which an invention shall fulfil to get a patent and Section 3[1] of the Indian Patents Act, 1970, which provides a list of inventions which are non-patentable under section 3 (d) of the Act. Section 3(b)[2] restricts the grant of patents for inventions which are injurious to life forms and the environment. Here, the question arises: to what extent can an invention be considered injurious enough to be denied patentability? This article establishes a connection between morality and patents. Further, it aims to clarify the ambiguous words of the provision by analysing the case of Harvard Oncomouse.
Introduction
In today’s age, the scope of Intellectual Property Rights (IPR) is expanding exponentially with the aid of extensive technology and modern equipment. IPR is a concept that is recognised worldwide, granting rights and protection to various established fields of Intellectual Property (IP) such as Copyright, Patents, Trademarks, Designs, Geographical Indications, Semiconductor Integrated Circuits, Plant Varieties and Biological Diversity in order to facilitate fair trade and safeguard the intellectual labour, all while upholding public policy[3].
In India, the law of patents is governed via the Indian Patents Act 1970, with notable amendments in 2002 and 2005. A patent is an exclusive right granted to the true and first inventor of an invention for a period of 20 years from the date of filing. Section 2(1)(j)[4] of the act defines “invention” as a new/novel product or a process that includes an inventive step and is capable of industrial application. The invention also includes an improvement capable of independently meeting the aforestated criteria. Section 2(1)(j)[5] defines inventive step as technical advancement, having economic significance, or both compared to existing knowledge.
It’s not necessary that when a subject matter qualifies all the three criteria of patentability it will benefit society. Hence, various provisions under the act, such as section 3[6] and section 4[7] of the act, lay out criteria for inventions disqualified from grant of patent. In this article, we will understand the bar on the patentability of an invention when it causes some serious prejudice to a life form, against public order and morality.
Morality and Public Policy in Patent
Morality and public policy have a significant role in patents. First of all, the right to patent is granted to the inventor in order to reward his/her intellectual labour fairly. Then the exclusive right protection lasts for a period of 20 years so that upon its expiry, the invention is available to the public at large, and society can also benefit from it. Further, we witness provisions of compulsory licensing (Sections 82 to 94), surrender and revocation of patents (Sections 63 to 66), Section 47[8], and the use and acquisition of patent by the Central Government for their own use; these provisions govern the use of patents on the basis of public policy and morality.
Amendment of 2002 in the Patent Act, 1970
Article 27[9] of the Trade-Related Aspects of Intellectual Property Rights Agreement (TRIPS) establishes general principles of patentability. The exclusion part of the second clause grants member countries certain rights to exclude the following inventions from patentability to protect public order and morality. They include any inventions contrary to human, plant, animal and environment, not limited to exposition defined and barred by the law[10].
Section 3[11] of the act is very important as it lays out a negative list, stating the products or processes that won’t be considered as an invention, despite qualifying the essentials of the patent criteria. Section 3(b)[12] of the act was amended in 2002 to incorporate the regulations laid out in Article 27[13] of TRIPS; it states that any invention whose primary use or intended use or commercial exploitation would go against the public order or morality or the invention causes serious prejudice to human, animal or plant life or health or to the environment will not be considered as an invention. Examples: inventions related to theft, gambling, human cloning, etc.
Harvard Oncomouse Case[14]:
Facts
In the early 1980s a group of researchers at Harvard Medical School invented one of the world’s first transgenic mice for furthering cancer research. They induced an oncogene in the mouse’s DNA, which made the mouse vulnerable to cancer and develop tumours. The creators of “Oncomouse”, on behalf of the institution, filed for a patent in the USA, Canada and the European Patent Office (EPO)[15].
Issues Raised
- Upon meeting the essential patentability requirements, should parents be granted regarding living animals and their varieties, specifically for higher stature animals such as mammals?
- How should moral implications and public policy be affected in regard to transgenic animals and their suffering?
The case was fought in various jurisdictions, and each country has given different perspectives on the issues raised[16].
United States of America
Harvard University was granted a patent by the US Patent Office in the year 1998. It described the mouse as “a transgenic non-human mammal whose germ cells and somatic cells contain a recombinant activated oncogene sequence introduced into said mammal or an ancestor of said mammal, at an embryonic stage…”. The matter of patents on human beings and modifications to the human genomes was explicitly excluded, considering the legal and moral concerns[17].
European Patent Office
The oncomouse case was considered at length in front of the European Patent Office (EPO), and the final decision was given by the Appellate Board in 2004. The board applied Article 53(a)[18] which states non-grant of a patent for “inventions the commercial exploitation of which would be contrary to “ordre public” or morality; such exploitation shall not be deemed to be so contrary merely because it is prohibited by law or regulation in some or all of the Contracting States” and Article 53(b)[19] stating non-grant of patent for, ”plant or animal varieties or essentially biological processes for the production of plants or animals; this provision shall not apply to microbiological processes or the products thereof”.
The EPO stated that the oncomouse didn’t qualify under the definition of animal variety, and so it doesn’t qualify under Article 53(b)[20]. It was further stated that a ban on patenting “animal varieties” under the article didn’t implicate a ban on the patenting of animals.
The EPO came up with the Utilitarian test in order to address and balance public order & morality. The test was set out to compare positive aspects with the negative ones. In this case, the positive aspect was the benefits occurring from the use of oncomouse in furtherance of cancer research for humans and was weighed against the morally negative aspect of suffering caused to the oncomice.
In furtherance of the test, other factors were also considered, such as environmental harm, which turned out to be neutral and public discontent, which was also recorded as neutral after considering the evidence based on European demographics.
Thus, the EPO gave its judgment in favour of granting of patent to the oncomouse. Since the test results specified that the positive aspects and utility of oncomouse in furtherance of cancer research greatly overpassed the negative aspect of morality and suffering caused to the oncomice.
Later, in 1992, Upjohn Pharmaceuticals put a similar case of genetically modified mice before the EPO. In this case, the transgenic mouse was being used to advance the treatment of human baldness and wool production mechanisms. This infusion resulted in the loss of all hair in the mouse. EPO used the same utilitarian approach to weigh out the positive aspects and negative aspects, but here, the latter prevailed over the former. The mouse was not guaranteed patent as it was against morality, and the use wasn’t as essential as oncomouse[21].
Canada
When the case was filed in the Canadian patent office, the patent officer rejected the request for patent prima facie on the basis that their law didn’t include animals in the definition of the invention. Regardless, another claim on the patent process for producing the oncomouse was allowed to go forward.
The Supreme Court of Canada gave its final verdict in the year 2002. The court stated that higher life forms and mammals were not subject to the definition of the invention, which mainly focuses on the manufacture or composition of matter, as per the Patent Act 1869. The act previewed “Manufacture” as a non-living mechanical product or a process and “Composition of matter” as a mixture of ingredients or substances by a person. The judges distinguished that the lower life forms were subjected to the composition of matter while the higher life forms were disqualified. So, the court qualified microorganisms and transgenic animals as a composition of matter and approved a patent while rejecting the patent claim on the body of the oncomouse.
The court pointed to the Patent Act, 1869, and stated that the drafters left out the subject matter of the patentability of higher life forms while drafting the act. The court recommended that the patentability of life higher forms was very controversial and the parliament must engage in a public debate to discuss the subject matter’s social standpoint, morality and legislative stance. The court concluded by stating that, scientific alteration of the genetics of an animal (not a higher life form), which doesn’t exist in nature in that altered form, will qualify under “composition of matter” under the Patent Act[22].
Conclusion
Creating and patenting transgenic animals proposes a moral and ethical dilemma in the field of patents. The oncomouse case showcases the diverse reasoning and standpoints of various jurisdictions across the world. The case has outlined patentability requirements, patentable subject matter and ethical dimensions of patentability on life forms which stand controversial with public order. It can be concluded that patentability of higher life forms, such as mammals, is barred across the world as of now. In India, Section 3(b)[23] of the Patent Act, 1970 doesn’t allow an invention to be patented that will drastically affect humans, plants, environment while going against public policy or morality. Upon hitting Section 3(b)[24] of the Indian Patent Act, 1970, the inventor must prove to the controller that the invention’s positive aspects outweigh the negative aspects and ensure he/she has taken the necessary steps to minimise the negative effects, then only the invention will have a chance to be patented, subject to discretion of the controller of patents.
Author: Hardik Manwani, UPES Dehradun
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Apr 7, 2024 | General
Recognising Odisha’s culinary heritage, the beloved delicacy known as “Kai Chutney” has been bestowed with the prestigious geographical indication (GI) tag under the Geographical Indications of Goods (Registration and Protection) Act, 1999[1]. Hailing from the Mayurbhanj district, this savoury condiment from red weaver ants stands out for its unique cultural significance and remarkable health benefits.
Weaver ants, scientifically known as Oecophylla smaragdina, play a central role in the creation of Kai Chutney. These industrious insects are commonly found in Mayurbhanj throughout the year, crafting nests from the leaves of host trees. Their nests, ranging from small single-leaf structures to large elliptical formations, demonstrate impressive resilience against wind and water.
The culinary journey of Kai Chutney begins with the careful collection and cleaning of red weaver ants from their forest habitats. Tribal communities, deeply rooted in this age-old tradition, sustain their livelihoods by harvesting these insects and crafting the renowned chutney. The preparation process involves grinding a blend of salt, ginger, garlic, and chillies with the collected ants and their eggs, resulting in a flavorful and aromatic paste.
But Kai Chutney is more than just a culinary delight; it’s also celebrated for its numerous health benefits. Packed with essential nutrients such as protein, calcium, zinc, and vitamins, this unique condiment offers a natural boost to one’s well-being. It is believed to alleviate ailments like flu, common cold, and whooping cough while enhancing appetite and vision.
Beyond its nutritional value, Kai Chutney holds cultural significance among the tribal communities of Odisha. It serves as a symbol of tradition and heritage, embodying centuries-old practices passed down through generations. Additionally, integrating red weaver ants into the diet showcases a sustainable approach to food production, offering an eco-friendly alternative to conventional livestock farming.
With its recent recognition through the GI tag, Kai Chutney stands as a testament to the rich culinary diversity of Odisha and the innovative utilisation of local resources. As this beloved condiment continues to captivate taste buds and promote well-being, it reinforces the importance of preserving and celebrating indigenous food traditions[2].
Author: Gayatri Singh, UPES, Dehradun
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Mar 27, 2024 | Patent
In simple words, patent infringement is the violation of patent rights of a patentee in the country or jurisdiction where the patent has been granted. This violation happens when any third party, makes, uses, sells, offer for sale, a product or process claimed in the patent, granted to the patentee without his/her authorization or license. When a patent is granted, the patentee gets the right to prevent third party (ies) from making, using, selling, offering for sale or importing the patented product in the country where there is patent protection.
To avoid patent infringement, it is highly recommended for the business owners to examine existing patents before launching their new products to ensure that no patent rights are violated in the territory where their product is going to be launched. This investigation to assess patent infringement risk is called as Freedom to Operate (FTO) analysis or clearance search.
How is FTO performed?
Purpose of FTO search is to assess the likelihood of patent infringement upon launch of new product in a specific market. The best time to perform FTO search is at the time of designing the new product because it is easier to make changes in the product specifications and the infringement risk can be minimised or nullified easily at early stage of product development. FTO is a very specialised investigation and analysis of patent documents, done by a skilled attorney, who possesses a good working knowledge of technology as well as law. The final opinion on infringement shall always be rendered by an advocate according to the laws of the jurisdiction. Generally, following steps are taken up to perform FTO analysis:
- Identification of components of the product to be launched and listing out nomenclature of the components, as generally used in the industry.
- Performing a patent search with all possible synonyms of the product component names along with other search techniques to pull all relevant patents with a timeline of 20-22 years. Patent search here may be global or country-specific depending upon the countries in which the product is going to be launched or sold. The business owner must be very focused and specific with respect to patent search strategies to ensure that the right data is extracted.
- For FTO search, generally only “in-force” or live patents are analysed. Therefore, considering very old and expired patents may not be of much use for FTO search. However, expired patents may be extremely helpful to find out technologies or products for which patents have expired. Even though expired patents may not impose any infringement risk but they can certainly provide valuable information otherwise.
- After the relevant patent documents are extracted, it is important to segregate them as “expired”, “abandoned” or “in-force” patents. Further, there may be a need to separate out the patent applications and the granted patents. If there are any risky patent applications, it is highly recommended to monitor them periodically to find out the kind of objections that the examiner raises during prosecution and to know if patent application gets granted as a patent or not.
- Further, during performing FTO search, if there are any “lapsed patents”, there may be chance of restoring such lapsed patent. Therefore, the legal status of lapsed patent shall be checked periodically and the risk it imposes shall be completely ruled out only after the timeline to restore has lapsed and its legal status reflects as “Expired”.
- Patents so extracted during the search shall be analysed in detail by comparing claims of the patents with product features. Generally, patent practitioners prepare claim maps where the portions of the claims with match or overlap with product components are highlighted. Based on the extent of overlap between patent claims and the product components, the patent documents may further be considered as low, moderate or high-risk patents.
How to handle high-risk patents?
In case the FTO analysis reveals high risk patents, using such patents may be detrimental for the business. Following points may be taken into consideration before using such patents:
- Check expiry date of the patent. If the patent is going to expire soon, it is worth to wait for the patent to expire before using it.
- Carefully read and analyse patent claims and try to understand what is claimed. Often the language used in the claims is very complex and expert advice must be sought.
- Perform invalidation search to understand how strong the patent is. This search is performed to identify the grounds on the basis of which a patent may be invalidated. Generally patent search is performed to reveal closest prior art and novelty/inventive step is assessed.
- Based on the outcome of invalidation search, opposition to the grant of patent, if patent is not yet granted; or post-grant opposition or even revocation may be filed. The opposition petition shall have all possible statutory grounds of opposition, which help the Controller of Patents to give decision on invalidating or revoking the patent.
- In case there is no other way out, obtaining license to use the patent may be obtained from the patentee. This option may not be feasible in most of the cases as granting license is at sole discretion of the patentee.
Above listed are few ways to handle a situation where there is a high risk of patent infringement. If none of the step’s work, it is advisable not to use the patent because if patentee takes a legal action, it may be detrimental for the reputation and good will of the business. In Merck vs. Glenmark case, the Delhi High Court passed an injunction against Glenmark for manufacturing the generic drug Sitagliptin and using patented product of Merck as there was prima facie infringement of patent rights of Merck. Delhi High court passed injunction order against Glenmark from manufacturing and selling of Zita and Zitamet. Thereby, patent rights of Merck were protected and enforced.
Patent infringement risk assessment and mitigation shall be integral part of steps to be followed before new product launch. FTO search can be extremely helpful to understand extent of infringement risk and to take right measure to minimise it.
Author: Bindu Sharma, CEO, Origiin IP Solutions LLP
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Mar 14, 2024 | Patent
Patent pruning is a process of analysing the patent portfolio of a company or an institution to identify, categorize, and optimize the patents. The analysis & pruning of the patent portfolio helps to identify and categorize the low-quality patents, so that the low-quality patents are discarded to strengthen the overall worth of the patent portfolio.
Patent pruning refers to the process of refining or simplifying a patent application by removing unnecessary or redundant elements while retaining the essential features and claims. This process aims to improve the clarity, focus, and strength of the patent, making it more likely to be granted and enforceable. Patent pruning process facilitates optimization of the patent portfolio of a company, wherein discarding low-quality patents can prevent the wastage of resources used in the maintenance of low-quality patents for a company and ultimately helps save significant amounts of money. The main benefit of the patent pruning process is cost saving, where a company can substantially reduce the patent maintenance cost by categorizing low-quality and high-quality patents. Let’s discuss the process involved in Patent Pruning.
- Patent Pruning process
It is essential to understand the process involved in patent pruning and the importance of patent pruning, to effectively execute the identification and categorization of patents. The patent pruning process involves:
- Patent indexing and categorization: The process of patent pruning starts with the indexing of patents and then categorizing them into core and non-core patents. More structured categorization and indexing of patents may be done by performing an IP Audit. Identifying and categorizing a company’s patents into core and non-core patents involves determining the patents that are related to a company’s core technology and products and the patents that are not so related to the company’s core technology. Further, along with determining the core and non-core patents, sides core and non-core classification, the patents can be shortlisted based on the market performance and future scope of the invention.
- Patent Mapping: Mapping the patents helps to understand the valuable core patents that can promote and protect the company’s business. Mapping the patents related to profitable end products and important sectors helps in analysing the core patents of higher value.
- Patent Grouping: After categorizing the patents, the patents of interest are grouped for further analysis, wherein the grouped patents can be related to core technology having profitable end products. Grouping of similar patents may be achieved by using patent landscape techniques.
- Patent Sorting: The sorting of the patent groups can be achieved based on various parameters, including the life of the patents, family size of the patents, citations per year, forward citations and self-citations of the patent etc. Based on these parameters, the grouped patents are sorted to discard the low-quality patents and optimize a company’s patent portfolio.
The life span of a patent is generally 20 years and in order to complete the life span, the patent has to be renewed by paying the required renewal and maintenance fee. As the term of a patent increases, the maintenance fee also increases. Hence, it is very important to identify the relevant and important patent groups to save unnecessary costs spent on patent renewal on low-quality patents. The analysis of patent life for the patent groups is highly critical as the industrial applicability of the patent for 20 years and its relevance for the complete life span helps to prune the irrelevant patents.
Further, the family size of a patent is important as it identifies the patent families comprising a large number of patent members, and it is to be noted that patents with a large number of patent members involve larger filing and maintenance fees. Another important parameter is the citations per year, wherein analysing the patent citations per year helps determine the patents with more citations per year, indicating that the patent has higher market potential. Such patents are important for a company as the increasing market potential indicates that such patents can prevent competitors from entering the market.
The next important parameter is the forward citations and self-citations of a patent, wherein the forward citations help determine the importance of a patent as the patent is cited by the competitors of the same domain. When a patent has a significant number of forward citations, the patent possesses great potential. And similarly, the patents with a very low number of forward citations are low-quality patents, and can be discarded, abandoned, sold or licensed. The self-citation of a patent is done when a patent cited by a company is of higher value. The number of self-citations of a patent determines if the technology protected by a patent is important for a company.
The sorting of the patent groups enables the companies to categorize the irrelevant patents clearly, and the irrelevant patents should be pruned to optimize the patent portfolio.
After completing the patent pruning process, the companies must effectively maintain their patent portfolio by conducting the pruning more often, leading to the selection of high-quality patents, and the selected high-quality patents are maintained, and low-quality patents are discarded.
- Patent pruning frequency
Knowing how frequently a company must run the patent pruning process is important. Companies can select their patent pruning frequency based on the number of patents they filed and their profits. Generally, big companies conduct the patent pruning process monthly. The pruning process can be conducted monthly, quarterly or yearly.
Pruning a patent portfolio is often necessary for several reasons:
- Cost Reduction: Maintaining a large patent portfolio can be costly in terms of maintenance fees and administrative overhead. Pruning allows companies to reduce these expenses.
- Focus on Core Technologies: Companies may choose to focus their patent efforts on technologies that are most relevant to their business strategy and goals. Pruning helps to streamline the portfolio in alignment with these priorities.
- Avoiding Infringement Risks: Some patents may carry risks of infringement claims against the company. By pruning patents that pose such risks, companies can reduce their legal exposure.
- Enhancing Portfolio Value: A leaner, more focused patent portfolio can be more attractive to potential buyers or licensees, potentially increasing its overall value.
- Adaptation to Market Changes: Technologies and markets evolve over time. Pruning allows companies to adapt their patent portfolios to reflect these changes and stay competitive.
Conclusion
The patent pruning process is critical in maintaining a company’s patent portfolio. Pruning the low-quality patents enables the companies to identify, categorize and optimize their patents, thus increasing the overall value of their patent portfolios and reducing the cost involved in the maintenance of the irrelevant patents.
Author: Megha S Nadiger, Origiin IP Solutions LLP
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Mar 14, 2024 | General
Diabetes is rapidly becoming a major global health crisis in the 21st century. There are currently 537 million persons between the ages of 20 and 79 who are living with diabetes, which is equal to 10% of the world’s population [1]. It is predicted that the number of individuals with diabetes will increase to 643 million by 2030, and further to 783 million by 2045 [2]. Diabetes is responsible for the majority of neuronal damage, visual impairment, and kidney failure in the non-elderly population. Approximately half of diabetic peripheral neuropathies (DPNs) may not exhibit symptoms, underscoring the importance of comprehensive screening, as neglecting foot care measures heightens the likelihood of harm.
Diabetic neuropathy, a condition characterized by high prevalence and disability, poses significant challenges in terms of management. These challenges include various complications, which not only burden individuals but also incur substantial financial costs. Diabetic foot is a significant factor in the global burden of disability and decreased quality of life. 14 -24% of diabetic foot patients require major or minor lower limb amputations [3]. There are 70 million diabetics in India out of which 50% have diabetic peripheral neuropathy and nearly 25-34% of them develop diabetic foot ulcer (DFU) and 1.2 million need special care for DFU [4]. The 5-year survival rate of diabetic foot patients with major amputations is 30%. There are 100000 registered amputations per year due to diabetes in India [5].
Additionally, individuals with a prediabetic status are more likely to develop DN at an earlier stage. The main complication associated with peripheral sensory neuropathy is the development of DFUs and subsequent minor or major amputations. Research has indicated that having underlying peripheral neuropathy raises the risk of any amputation by 1.7 times [6]. The risk increases by a factor of 12 if there is a deformity (caused by motor neuropathy) and increases significantly to 36 times if there is a previous history of ulcers.
Classifications of DPN
The primary categories of neurologic disorders in DM encompass:
- Subclinical neuropathy is determined by abnormalities in electrodiagnostic and quantitative sensory testing
- Diffuse clinical neuropathy with distal symmetric sensorimotor and autonomic syndromes.
- Sensory or sensorimotor polyneuropathy
- Selective small-fibre polyneuropathy
- Autonomic neuropathy
- Focal syndromes:
- Truncal mononeuropathy
- Mononeuritis multiplex
- Asymmetric lower limb motor neuropathy (amyotrophy)
- Cranial neuropathy
- Mixed forms
Subclinical neuropathy is identified when there are no clinical indications of neuropathy, but abnormal electrodiagnostic tests show reduced nerve conduction velocity (NCV) or amplitude; quantitative sensory tests (QSTS) reveal altered perception of vibration, touch, and temperature; and autonomic function tests (AFTs) indicate dysfunction in sympathetic and parasympathetic nerves.
Risk factors for peripheral neuropathy
The risk factors for the development of diabetes-related peripheral neuropathy are as follows:
The risk factors with a major impact are:
- Poor control of blood sugar levels
- Long-standing diabetes
- Damage to blood vessels
- Alcohol consumption
- Metformin use
The risk factors with a minor impact are:
- Autoimmune factors
- Genetic susceptibility
- Smoking
- Low levels of high-density lipoprotein (HDL)
- Cardiovascular disease
A study found that the duration of diabetes mellitus (DM) is a major risk factor for neuropathy. Patients with DM for more than 15 years have an odds ratio of 8.03 (95% confidence interval 5.96-10.8, p<0.001) for developing neuropathy compared to those with a duration of less than 5 years [7]. The study also found that increasing age, the presence of dyslipidemia, and the presence of other microvascular complications are significantly associated with peripheral neuropathy (Fig.1).
Pathogenesis of peripheral neuropathy
The pathophysiology of diabetic peripheral neuropathy is multifactorial and is thought to result from vascular disease occluding the vasa nervorum; endothelial and myelin synthesis dysfunction and diminishing sodium-potassium adenine triphosphatase (ATPase) activity; chronic hyperosmolarity, causing oedema of nerve trunks; and effects of increased sorbitol and fructose.
Nonenzymatic glycation predisposes ligaments to stiffness. Neuropathy causes loss of protective sensation and loss of coordination of muscle groups in the foot and leg, both of which increase mechanical stresses during ambulation.
Motor dysfunction of peripheral nerves in diabetic neuropathy leads to muscular imbalances in the diabetic foot. Muscle wasting of the intrinsic pedal muscles leads to overpowering of the spared extrinsic muscles, which results in significant forefoot deformities such as claw toes or hammer toes. Autonomic dysfunction of the peripheral nervous system may lead to sudomotor dysfunction. This will result in dry, cracked skin, and intrinsic minus foot, which is more prone to injury and breakdown.
The result of loss of sensation in the foot is repetitive stress; unnoticed injuries and fractures; structural foot deformity, such as hammertoes, bunions, metatarsal deformities, or Charcot foot; further stress; and eventual tissue breakdown.
Unnoticed excessive heat or cold, pressure from a poorly fitting shoe, or damage from a blunt or sharp object inadvertently left in the shoe may cause blistering and ulceration. These factors, combined with poor arterial inflow, confer a high risk of limb loss on the patient with diabetes.
Metabolic Hypothesis
Chronic hyperglycemia cause damage to peripheral nerves through various pathways, one of which involves an increase in the entry of polyol that is regulated by aldose reductase, also known as the polyol pathway. Another theory suggests that injury to the endoneurium of peripheral nerves is caused by an excessive build-up of advanced glycation end-products (AGES). Additionally, hyperglycemia contributes to peripheral neuropathy by generating oxidative stress-induced free radicals during the glycolytic process ( Fig.2 and 3).
Immune Hypothesis
In patients with DN, the presence of antiphospholipid antibodies and autoantibodies to gangliosides indicates a potential role of these factors in the development of DN.
Microvascular Hypothesis
Nerve ischemia is caused by microvascular insufficiency resulting from inadequate blood supply to the vasa vasorum. This insufficiency is contributed by an increase in the thickness of the vessel walls, hyalinization of the basal lamina, and impaired vasoconstriction and vasodilation.
Neurotrophic Hypothesis
Patients with DN exhibit a deficiency in neurotrophic factors such as nerve growth factor (NGF), neurotrophin-3/4/5, and insulin-like growth factor (IGF)-1
Clinical evaluation
The neuropathic symptoms are divided into focal and diffuse forms, of which the latter is far more common .
Diffuse Neuropathies
One should look for specific motor and sensory symptoms in patients as it helps in understanding the underlying nerves at fault. This can be understood from the following:
Acute Painful Neuropathy
Some patients with diabetes mellitus (DM) present with acute symptoms that persist for less than six months and are accompanied by moderate-to-severe pain. The pain caused by sensory neuropathy worsens at night and is often more pronounced in the feet than in the hands. As a result of the nocturnal pain, patients frequently complain of sleep disturbances and insomnia. The nature of the pain can be described as burning, stabbing, tingling, pins and needles, paresthesia, or a prick sensation.
In this scenario, the following possibilities should be considered:
– Insulin neuritis – Rapid correction of blood glucose levels – Chronic alcohol consumption – Associated amyloidosis and multiple myeloma – Human immunodeficiency virus (HIV) infection – Heavy metal poisoning (e.g., arsenic) – Fabry’s disease
Chronic Painful Neuropathy
Chronic painful neuropathy is a separate condition that typically develops later in individuals who have been diagnosed with DM for several years. In this case, the debilitating pain persists for more than six months.
Over time, many patients may experience a lack of pain, which is not necessarily indicative of symptom improvement, but rather due to neuronal loss. Hyperalgesia, on the other hand, refers to an increased perception of pain even in response to normal stimuli. Allodynia is the sensation of pain caused by a stimulus that is not typically painful.
The sensation of burning and pricking is attributed to C and Ao fibers, while Aẞ fibers are responsible for dysesthesias, paresthesias, and allodynia.
Large-fiber neuropathies
Large-fiber neuropathies affect the sensory or motor nerves. These neuropathies display more signs than symptoms. Fiber neuropathies cause changes in vibration perception, position sense, and cold thermal perception. These myelinated, rapidly conducting fibers primarily affect the toes rather than the fingers, as they are length-dependent fibres that are more noticeable in electromyography (EMG). The alteration of these fibres leads to a sensation of walking on cotton in the feet and, in severe cases, difficulty in distinguishing shapes and turning pages in books.
The clinical presentation of large-fiber neuropathies includes:
- Impaired vibration perception (often the first objective evidence) and position sense
- Decreased tendon reflexes.
- A deep-seated gnawing pain similar to a toothache in the bones of the feet, or even a crushing or cramp-like pain
- Wasting of the small muscles in the feet, resulting in hammer toes.
- Shortening of the Achilles tendon, leading to pes equinus.
- Increased blood flow, causing warm foot
Proximal motor neuropathies
Proximal motor neuropathies, also known as femoral neuropathy, diabetic amyotrophy, and diabetic neuropathic cachexia, have distinct symptoms and signs. This condition primarily affects the elderly, typically occurring after the age of fifty. The onset of symptoms can be gradual or abrupt, beginning in one leg and progressing to the other. The initial symptom is often pain in the thighs, hips, or buttocks, followed by proximal myopathy. Interestingly, heel or toe standing is usually unaffected despite weakness in the proximal muscles. Patients may experience spontaneous or provoked fasciculations, and electromyography (EMG) often reveals features of lumbosacral plexopathy. While proximal motor neuropathy is commonly associated with diabetes mellitus, it is important to consider other potential causes such as chronic inflammatory demyelinating polyneuropathy (CIDP), monoclonal gammopathy of unknown significance (MGUS), circulating GMI antibodies, and antibodies to neuronal cells and inflammatory vasculitis. If demyelination is the predominant finding on EMG, further investigation into causes other than diabetes mellitus is warranted, as the treatment options may differ in cases of femoral neuropathy.
Asymmetric neuropathies
Mononeuropathy
- Generally acute with pain.
- Usually in older population.
- It can involve truncal and cranial nerves (III and VI).
- Self-limiting and resolving in 6-8 weeks.
- Usually due to vessel occlusion.
- Treatment: Symptomatic for pain and physiotherapy.
Entrapment neuropathy
- Starts slowly and progresses slowly.
- Commonly involves the median (carpal tunnel), ulnar, radial, femoral, and lateral cutaneous nerve of the thigh.
- Treated with splints, nonsteroidal anti-inflammatory drugs (NSAIDs), and local injection.
- In some cases, surgery to decompress.
Mononeuropathies must be distinguished from entrapment syndromes, which start slowly, progress, and persist without intervention.
Nerve conduction studies
Electromyography-nerve conduction velocity (EMG-NCV) has become a crucial technique for tracking the early development and progression of peripheral neuropathy. These measures are objective, quantitative, noninvasive, and highly sensitive. The primary purpose of EMG is to distinguish between diabetic neuropathy and neuropathy of non-diabetic origin. Studies have rep that patients with an average HbA1c level >10% over an 8-year period exhibited a significant decrease in NCV.
Newer techniques
Newer techniques for evaluating small-fibre function include the use of:
- Corneal confocal microscopy, which allows the identification of unmyelinated axons in the cornea.
- Sudomotor function devices.
Treatment
Small fiber neuropathy
In order to manage the condition, it is important to engage in certain practices. For example, daily inspection of the feet is necessary, and using a handheld mirror to examine the soles of the feet can be helpful. It is also crucial to wear well-fitting Microcellular rubber (MCR) shoes to ensure comfort and prevent further complications. Additionally, it is advised to avoid exposing the feet to extreme temperatures. To combat skin drying and cracking, the use of moisturizing creams is recommended. After bathing, it is essential to thoroughly dry the feet. When it comes to nail care, cutting them transversely is the recommended approach.
Large Fiber Neuropathy
In patients with DM and large fiber neuropathy, it is important to focus on gait and strength training. This is because individuals with this condition have an increased risk of falls due to sensory ataxia, weakness, incoordination, muscle wasting, and the possibility of fractures following falls. This is particularly true for post-menopausal women. Therefore, enhancing muscle strength is crucial in order to prevent complications related to DM and small fiber neuropathy. Microcellular rubber (MCR) footwear is the most commonly used material for patients with DM and peripheral neuropathy. It is recommended to use footwear with a shore value between 8 and 15 for those with DM. MCR footwear has proven to be effective in preventing the development and recurrence of ulcers.
Pharmacological treatment
Many prescription medications are available for diabetes-related nerve pain. Pain-relieving prescription treatments may include:
Anti-seizure drugs. Some medications used to treat seizure disorders (epilepsy) are also used to ease nerve pain. The ADA recommends starting with pregabalin (Lyrica). Gabapentin (Gralise, Neurontin) also is an option. Side effects may include drowsiness, dizziness, and swelling in the hands and feet [8].
Antidepressants. Some antidepressants ease nerve pain [8]. Tricyclic antidepressants may help with mild to moderate nerve pain. Drugs in this class include amitriptyline, nortriptyline (Pamelor) and desipramine (Norpramin). Side effects can be bothersome and include dry mouth, constipation, drowsiness and difficulty concentrating. These medications may also cause dizziness when changing position, such as from lying down to standing (orthostatic hypotension). Serotonin and norepinephrine reuptake inhibitors (SNRIs) are another type of antidepressant that may help with nerve pain and have fewer side effects. The ADA recommends duloxetine (Cymbalta, Drizalma Sprinkle) as a first treatment. Another drug that may be used is venlafaxine (Effexor XR). Possible side effects include nausea, sleepiness, dizziness, decreased appetite and constipation. Sometimes, an antidepressant may be combined with an anti-seizure drug. These drugs can also be used with pain-relieving medication, such as medication available without a prescription. For example, one may find relief from acetaminophen (Tylenol, others) or ibuprofen (Advil, Motrin IB, others) or a skin patch with lidocaine (a numbing substance).
Conclusion
Diabetic peripheral neuropathy is a multifaceted complication of diabetes that involves intricate pathological processes and interactions between various cellular and molecular factors. An in-depth understanding of the underlying pathophysiology is crucial for physicians, enabling them to adopt a targeted approach in diagnosing, treating, and managing DPN effectively. By addressing the pathogenic mechanisms discussed above, healthcare professionals can work towards developing novel therapeutic interventions and significantly improve patient outcomes in DPN management.
Author: Dr. Sanjay Sharma, MS, Diabetic Foot Surgeon
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