Carpal tunnel syndrome (CTS) occurs when the median nerve becomes entrapped when passing through the carpal tunnel bound by the transverse carpal ligament and the carpal bones [7]. The median nerve carries the sensory fibers that supply the first three fingers and the lateral side of the fourth finger. Therefore, the classic manifestation of CTS is pain and/or paresthesia in the median nerve territory. These sensations can propagate proximally into the forearm and elbow. In more severe cases, the motor function of the median nerve is also impaired, leading to weakness in the abduction and opposition of the thumb and thenar atrophy. CTS is associated with repetitive hand and wrist movements and chronic pressure to the palm and wrist. Other risk factors include diabetes, obesity, hypothyroidism, and amyloidosis. CTS is a common disorder, with an estimated prevalence of 1% to 5% in the general population, and higher rates in older patients and those with obesity. It also has a predilection for the female sex, with a female-to-male ratio of 2-4:1 [5].

Bell’s palsy refers to acute idiopathic cranial VII nerve or facial nerve palsy and is the most common acute mononeuropathy. Its incidence ranges from 11.5 to 53.3 per 100,000 persons according to published epidemiological studies [8]. One Italy-based study found that the occurrence of Bell’s palsy increased with age, and another Korea-based study noted a peak incidence in the seventh decade of life [9,10]. Patients present with acute onset unilateral facial weakness or complete inability of movement, reaching maximum severity around 48 hours. When the sensory component of the facial nerve is involved, patients can also experience postauricular pain and altered taste. Most patients achieve a complete recovery of facial nerve function, but approximately 25% of patients may develop persistent paresis, contractures, or synkinesis (i.e., involuntary facial movements). The initial presence of complete facial paralysis, advanced age, and delayed signs of recovery (>3 weeks after symptom onset) are associated with a poorer prognosis [5,8].

The etiology of Bell’s palsy remains uncertain. Multiple mechanisms of facial nerve injury have been proposed, including mechanical compression from anatomical variations of the temporal bone through which the facial nerve traverses after exiting the brain stem, viral infections (especially of the herpesvirus family), and ischemia. The diagnosis of Bell’s palsy requires the exclusion of other causes of facial nerve palsy, such as trauma, malignancy, Ramsay Hunt syndrome, Lyme disease, and vascular insufficiency [8].

Shingles is a common disease, with an estimated incidence of 1 million cases per year in the United States [11]. It is caused by reactivation of the varicella zoster virus (VZV) that had remained dormant in the sensory ganglia after the initial infection. During an episode of shingles attack, VZV virions replicate within the residing neuron and travel down the axon to reach the skin innervated by the same neuron, causing the characteristic dermatomal blistering rash. Postherpetic neuralgia is a chronic neuropathic pain thought to be caused by inflammatory nerve damage as the body combats the reactivated VZV and can last months to years after the rash heals. It affects 5% to 20% of patients who have had shingles and its frequency increases with age, seen in 30% or more of patients over the age of 80. Prodromal pain and severe pain concurrent with the rash are additional risk factors for developing postherpetic neuralgia. Patients can experience constant or intermittent unprovoked pain, allodynia, or hyperalgesia over the same dermatome(s) as the shingles rash [11].

Mononeuritis multiplex typically presents with asymmetric sensorimotor neuropathy, where at least two nerves in different body parts are involved. The symptoms are diverse and can include sensory or motor deficits, as well as pain. The onset is often acute, and the progression is frequently rapid [5]. Mononeuritis multiplex is not a primary neurologic pathology, but rather the neurologic manifestation of another underlying systemic disease, most often vasculitis that has led to nerve ischemia [12]. Other diseases associated with mononeuritis multiplex include rheumatologic disorders (such as systemic lupus erythematosus and Sjögren syndrome), viral infections (such as coronavirus disease 2019 [COVID-19], hepatitis C, and human immunodeficiency virus [HIV]), diabetes, and sarcoidosis [5]. While the epidemiology of mononeuritis multiplex is unknown, it is expected to be seen in more older adults when an underlying disease such as giant cell arteritis (GCA) affects this population. PN has been seen in 19% of patients with GCA and 23% of patients with microscopic polyangiitis in a large multinational observational study [13].

Guillain-Barre syndrome (GBS) is the most common cause of acute flaccid paralysis, precipitated by an infection within 4 weeks prior to symptom onset in most cases [11,14]. It is thought that certain antigens on the pathogen structurally resemble some innate molecules in the peripheral nervous system, thereby triggering immune-mediated peripheral nerve demyelination and/or direct axonal injury. Infections associated with GBS include Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, influenza A, and arboviruses such as Zika virus [14,15]. The annual global incidence of GBS is quite low, at 1-2 per 100,000 person-years, and the frequency increases with age. GBS is clinically heterogeneous. The classic presenting symptom of GBS is ascending symmetric weakness that starts in the distal lower limbs. The weakness is rapidly progressive, peaking in approximately 2 weeks. Approximately 20% to 30% of patients can develop respiratory failure from the weakness and require intensive care. Hyporeflexia results from lower motor neuron damage. Sensory disturbance and pain frequently occur as well, sometimes preceding weakness, which could mislead the diagnosis. Autonomic fibers can also be involved and contribute to hemodynamic instability and cardiac arrhythmia. Recovery can take months, but most patients are able to walk independently 6 months after onset even without treatment. In most cases, GBS is a monophasic disease without relapse after recovery [1].

Diabetic neuropathy is the most common cause of PN in the developed world, accounting for 32% to 55% of all PNs across different populations [7]. The likelihood of developing neuropathy increases with the duration of diabetes and poor glycemic control, and 50% of patients with diabetes are expected to develop neuropathy along their disease course [16]. Most complications of diabetes, including diabetic neuropathy, are thought to be the results of vasculopathies stemming from chronic inflammation and the generation of advanced glycation end products. It has also been shown that diabetes impairs axonal regeneration after injury, which contributes to the lack of spontaneous recovery in most cases of diabetic neuropathy. There are multiple types of diabetic neuropathy that can also occur simultaneously.

Distal symmetric sensorimotor polyneuropathy accounts for more than half of diabetic neuropathy cases. Patients experience a gradual onset of sensory symptoms such as pain, numbness, and tingling in the distal limbs, creating a characteristic “stocking-glove” pattern [7].

Autonomic dysfunction is also commonly seen in patients with diabetes. Most epidemiological studies on diabetic autonomic neuropathy have focused on the cardiovascular subtype, which is characterized by impaired regulation of heart rate, decreased baroreflex sensitivity, and subsequent dysregulation of blood pressure leading to orthostatic hypotension. The reported prevalence of cardiovascular autonomic dysfunction varies widely, between 1% and 90%, among patients with diabetes. Diabetic autonomic neuropathy can also affect the vagus nerve and the enteric nervous system, potentially causing both abnormal stimulation (diarrhea and stool incontinence) and inhibition (gastroparesis and constipation) of the gastrointestinal tract. Urinary retention or urgency occurs when the genitourinary system is affected, and sleep apnea takes place when the respiratory system is involved [17].

Radiculoplexus neuropathy is another type of diabetic neuropathy. Diabetic amyotrophy, also known as diabetic lumbosacral radiculoplexus neuropathy, is thought to be an inflammatory process manifesting as microvasculitis that results in peripheral nerve ischemia. Patients present with acute onset unilateral pain, usually severe, and weakness in the proximal lower extremities associated with weight loss. Patients typically recover, at least partially, in months [16]. Mononeuropathy, such as oculomotor nerve palsy and CTS, can also take place in patients with diabetic neuropathy [5,16].

Paraneoplastic neurologic disorders (PNDs) are part of paraneoplastic syndrome, which is a group of non-metastatic complications of an underlying malignancy [5]. PNDs are rare, seen in <1% of cancer patients. All malignancies, except for primary central nervous system cancer, can produce neuronal antigens and trigger an autoimmune response against both the central and peripheral nervous systems. The cancers more commonly associated with PNDs are small cell lung cancer, breast cancer and gynecologic cancers. PNDs can affect all parts of the nervous system. Paraneoplastic PNs typically present with subacute onset of pain, numbness, and impaired proprioception in an asymmetric distribution. The much less common motor symptoms occur when either peripheral motor neurons or the neuromuscular junction (NMJ) is affected. Paraneoplastic peripheral motor neuropathy is driven by an acute inflammatory demyelination process, almost indistinguishable from GBS; whereas NMJ involvement often presents with gradual onset proximal muscle weakness, such as Lambert-Eaton myasthenic syndrome, a well-known NMJ disorder associated with small cell lung cancer caused by autoantibodies against the presynaptic voltage-gated calcium channels [18].

Paraproteins refer to the monoclonal immunoglobulins produced from plasma cell disorders, including monoclonal gammopathy of undetermined significance, Waldenstrom macroglobulinemia (WM), and multiple myeloma [19]. Overall, the incidence of plasma cell dyscrasia, and therefore the risk of associated polyneuropathies, increases with age. The immunoglobulin M (IgM) M-protein has a much stronger association with peripheral polyneuropathy than IgA and IgG immunoglobulins. The pathophysiology of paraproteinemia-associated PN is not clearly elucidated. Since IgM M-proteins have demonstrated reactivity against several molecules (e.g., myelin-associated glycoprotein and ganglioside) with abundant presence in the nervous system, it is postulated that upon binding to their ligands, the immunogenicity of the monoclonal immunoglobulins leads to inflammatory damage to peripheral nerves. While demyelination is the most common injury pattern, axonal injuries can also be seen, especially in WM [19].

The clinical presentation depends on the mechanism of nerve injury. In demyelinating cases, larger, myelinated sensory nerves are affected, causing gradual onset of distal, symmetric paresthesia and sensory loss. Ataxia can occur from sensory disturbance. Motor neurons, also myelinated, can be involved as well, albeit less frequently [5,19]. Axonal injury has more heterogeneous presentations, with sensory, motor, and autonomic symptoms.

Monoclonal gammopathy has a much higher prevalence (approximately 10%) in patients with idiopathic PN compared to the general population. It is therefore wise to evaluate underlying plasma cell disorders in patients with PN without another apparent cause, especially in older adults [12]. Clinicians should also keep in mind that the concurrent presence of monoclonal gammopathy and PN does not necessarily imply a causal relationship between the two diseases, and that treatment for plasma cell disorders could sometimes be the actual cause of PN [12,19].

All plasma cell disorders have the potential to cause primary amyloidosis, when excessively produced light chains aggregate to form insoluble fibrils that deposit in various organs such as the heart, kidneys, liver, and peripheral nervous system. The incidence of primary amyloidosis increases with age, and the median age at diagnosis is 64 years. Furthermore, 17% to 35% of patients with primary amyloidosis develop PNs [20]. In contrast with M-protein-associated PN, nerve damage in primary amyloidosis is not immune-mediated, but rather from mechanical compression, ischemia, and neuron apoptosis as direct results of amyloid deposition [12,19]. Since small fibers are affected, typical symptoms include distal paresthesia and pain, and autonomic dysfunction. CTS is commonly seen as well. Primary amyloidosis should be suspected when patients also present with renal dysfunction and heart failure alongside PN [12,20]. Transthyretin amyloid (ATTR), especially the wide type, is another form of systemic amyloidosis that affects older adults. Because peripheral nervous system involvement is rare, ATTR will not be discussed in this paper.

Multiple classes of drugs can cause PN by damaging neuron organelles and disrupting membrane ion channels. Medication-induced PN should have a clear temporal relationship with the initiation of the culprit medication. Chemotherapy agents are the most common offenders in older adults [21]. PN often becomes a dose-limiting side effect in about 30% of patients receiving chemotherapy [21]. Platinum-based agents, taxanes, and vinca alkaloids (especially vincristine) are well known to cause PN in a dose-dependent fashion [21]. Distal sensory neuropathy including pain, paresthesia, and decreased sensation is the predominant presentation with a gradual onset of weeks to months. Motor deficits are rare and only seen in cases of severe PN. While most PNs resolve gradually upon cessation of the causative medication, some can be persistent, such as cisplatin-induced chronic sensory neuropathy, where the medication accumulates in dorsal root ganglia and causes irreversible damage to neuronal DNA [21].

Immunotherapy has been rising in popularity in cancer treatment due to fewer side effects and better tolerability than cytotoxic chemotherapy. Immunotherapy inhibits checkpoints in the immune system and amplifies T cell activation to destroy cancer cells. This immune-boosting effect also increases the risk of autoimmune damage to organs, including the peripheral nervous system. Autoimmune PN occurs in <10% of patients receiving immunotherapy, but the incidence becomes much higher when multiple agents are used simultaneously. Any location within the peripheral nervous system can be affected, leading to diverse sensorimotor presentations including cranial neuropathies and GBS, usually with an acute to subacute onset [22].

PNs can also develop from non-antineoplastic agents such as anti-retroviral and antimicrobial medications at lower frequencies. In patients who take anti-retroviral medications, PN occurs at varying rates depending on the specific agent, most commonly with the use of zalcitabine, stavudine, and didanosine. These drugs are thought to impair mitochondrial DNA replication, thus depleting neurons of adenosine triphosphate supply and leading to axonal degeneration of sensory fibers and distal sensory neuropathy. Isoniazid, an anti-tuberculosis drug, also interferes with vitamin B6 metabolism. Vitamin B6 supplementation is co-administered with isoniazid to prevent PN development. Another anti-tuberculosis drug, ethambutol, causes optic neuritis by affecting mitochondrial functions in retinal ganglion cells. Thankfully, the associated vision loss is reversible in most cases. Rarely, metronidazole can also cause PN with prolonged use [23].

As the incidence of Parkinson disease (PD) increases with age, it should be mentioned that levodopa, the mainstay treatment for PD, can disrupt vitamin B12 metabolism, leading to the development of PN, especially at a daily dose >400 mg. The neuropathy is typically sensory and mild in severity [23].

Alcohol misuse is common among older adults. The 2005 to 2006 National Survey on Drug Use and Health found that 19% of men and 13% of women of age 50 and older consumed two or more drinks per day, and 14% of men and 3% of women of age 65 and older engaged in binge drinking. The number of older adults exhibiting problematic alcohol use is expected to increase with an aging population [24]. Alcohol-related PN can be seen in almost half of people with chronic alcohol dependence. They develop painful distal sensory neuropathy, mostly in the lower extremities with an insidious onset. The pathophysiology is multifaceted, including the direct neurotoxicity of alcohol, oxidative stress, and nutrition deficiency associated with long-term alcohol overuse [24].

Lead intoxication is now rare in developed nations. However, older adults have more exposure to environmental lead simply because they have lived longer. They are also more likely to have been in contact with lead-containing paint and gasoline before these materials were outlawed in the 1970s. Older adults are also at risk for more lead exposure from recreational activities like ceramic glazing and moonshine consumption [25]. Acute lead toxicity causes an acute motor-predominant neuropathy with weakness in finger and wrist extensors, whereas chronic lead neuropathy is mostly sensory. Concomitant cognitive impairment, gastrointestinal symptoms, and microcytic anemia with basophilic stippling frequently occur [25].

Vitamin B12 deficiency is common, affecting 5% to 20% of older adults, most often due to malabsorption such as in the case of atrophic gastritis or gastric bypass surgery. Other causes include low vitamin B12 intake and side effects of medications frequently used among older adults, such as metformin and proton-pump inhibitors [12,26]. Vitamin B12 deficiency leads to demyelination of large fibers, thereby impairing both sensory and motor functions. Demyelination can also occur in the central nervous system, affecting the corticospinal tract and dorsal column within the spinal cord and leading to subacute onset of sensory ataxia due to loss of proprioception [26].

Thiamine, or vitamin B1, plays crucial roles in neuron health maintenance and nerve regeneration when injury occurs. It serves as both an antioxidant and an essential coenzyme in energy production [27]. Since the body has extremely limited thiamine storage capacity, daily intake is essential. Older adults have significantly lower plasma levels of thiamine than younger people, regardless of comorbidities or medication use. This is due to inadequate intake and/or impaired absorption due to gastrointestinal lining atrophy. Chronic alcohol overuse is another noteworthy cause of thiamine deficiency [27]. PN due to thiamine deficiency is also known as dry beriberi. Motor symptoms including distal, facial, and laryngeal weakness are more common in the absence of alcoholism, whereas distal sensory neuropathy is the predominant feature when alcohol use disorder coexists with thiamine deficiency.