Therapeutic Options for Peripheral Neuropathy in Parkinson Disease

illustration of a Parkinson neuron
Parkinsons disease nerve cells. Computer illustration of human nerve cells affected by Lewy bodies (small red spheres inside cytoplasm of neurons) in the brain of a patient with Parkinsons disease. Lewy bodies are abnormal accumulations of protein that develop inside nerve cells in Parkinsons disease, Lewy Body Dementia, and some other neurological disorders.
The etiology and management of peripheral neuropathy in Parkinson disease is discussed.

Peripheral neuropathy is frequently seen in patients with Parkinson’s disease (PD) and may increase the functional disability in these individuals. A review article published in Neurological Sciences discussed the etiology of peripheral neuropathy in the context of PD.  

Previous studies have shown that peripheral neuropathy can adversely affect the lives of patients with PD. As limited data are available on small fiber neuropathy (SFN) and effective treatments for peripheral neuropathy in PD, the current review focused on the etiology, pathological mechanisms, subtypes, and management of the neurological problem in PD.

The exact pathogenic mechanism of neuropathy in PD is not entirely clear and there are many potential factors involved in the disease process, including medication, mitochondrial dysfunction, oxidative stress, and genetic susceptibility.


The diagnosis is based on clinical findings along with nerve conduction studies and electromyography. As some neuropathies may present with normal findings on peripheral nerves testing, a thorough patient history is vital.

The initial investigation of peripheral neuropathy often includes glucose tolerance testing, fasting glucose levels, measurement of vitamin B12, methylmalonic acid (MMA), homocysteine (Hcy), and serum protein electrophoresis.

The diagnosis of SFN is commonly difficult to be made on the basis of peripheral nerve testing and clinical criteria are more important. Intraepidermal nerve fiber density in skin biopsy or analysis of quantitative sensory testing can help in establishing the diagnosis. 

Additional tools that may aid in the diagnosis and severity assessment of SFN include autonomic testing utilizing a variety of reflex tests, intraepidermal electrical stimulation tests, corneal confocal microscopy, and microneurography.

Parkinson Disease Treatment and Neuropathy

Levodopa, the gold standard treatment for PD, may play an important role in the development of peripheral neuropathy .  Long-term use of levodopa can lead to increased levels of Hcy and MMA which have been linked to neuropathy, as well as increased risk for cardiovascular diseases, neurodegenerative diseases, and neural tube defects. While many studies have pointed at B12 deficiency as the potential cause for levodopa-associated neuropathy, others suggested that folate deficiency is a more important cause.

As not all patients taking levodopa develop neuropathy, experts have suggested there may be a genetic susceptibility for the development of neuropathy in some patients. Potential candidate genes involved in PN with PD may be the parkin or MTHFR genes.

Levodopa-carbidopa intestinal gel (LCIG) are additional treatment options that were found to be associated with peripheral neuropathy. Studies have suggested a higher incidence of neuropathy in PD patients treated with duodopa or LCIG. While limited data exist on the risk for SFN, there are reports suggesting an association between LCIG treatment with neuropathy of small fibers.

Administration of catechol-O-methyltransferase (COMT) inhibitors may attenuate the levodopa-induced increase in plasma Hcy and MMA levels. However, due to the limited available data, more studies are required to better understand the efficacy of COMT inhibitors in preventing peripheral neuropathy.

Treatments of Peripheral Neuropathy

The data on treatment of peripheral neuropathy in PD remain limited and additional studies are needed to explore the benefits of cobalamin injections with folate supplements and COMT inhibitors, especially in levodopa-treated patients. Novel treatment options include electromagnetic and laser therapy.

At this point in time, COMT inhibitors, such as entacapone, are the main treatment options for peripheral neuropathy. One study has shown that the addition of COMT inhibitors may improve levodopa-associated neuropathy.  However, as COMT inhibitors were not found to be effective against peripheral neuropathy secondary to causes other than levodopa exposure, other therapeutic options are needed.

Combination of vitamin B12 and methylcobalamin is recommended by some experts in the field and there are reports this may improve pain and paresthesia, but most of the data are based on studies in patients with diabetic neuropathy.

Several enzymes and genetic markers were suggested as therapeutic targets for peripheral neuropathy and have shown promising results. Furthermore, monoclonal antibodies may prove to be useful, as there are reports from patients with malignant tumors in which the combination of bendamustine-rituximab was found to alleviate immune-mediated neuropathies. Early reports have suggested a potential role for ultrasound guided vitamin B12 injections.

“Future studies should investigate the toxic effects of elevated Hcy and MMA levels in patients with PD along with viable treatment options that include vitamin B12 and folate therapy. Large scale studies are required in order to understand the role and efficacy of COMT-Is along with other IPD interventions in [peripheral neuropathy],” concluded the investigators.


Paul DA, Qureshi ARM, Rana AQ. Peripheral neuropathy in Parkinson’s disease [published online May 1, 2020]. Neurol Sci. doi:10.1007/s10072-020-04407-4