INTRODUCTION
Although Parkinson’s disease (PD) primarily affects the central nervous system, it
is a multi-organ disease which also affects the eyes and the peripheral nervous system,
including the autonomic fibers (1,2). PD-related disturbance of the peripheral nerves
may result in sensory, motor, or autonomic neuropathy. Autonomic dysfunction can manifest
as sicca syndrome, hypo-/hyperhidrosis, orthostatic hypotension, reduced blood pressure
variability, reduced heart rate variability, nausea, constipation, vomiting, urinary
dysfunction, or erectile dysfunction (1). Non-motor manifestations, such as hyposmia,
rapid eye movement sleep behavior disorder (RBD), constipation, or depression, may
precede these motor symptoms (1). Although PD-related neuropathy (PDRNP) is well recognized,
relatively little data about this topic are available. Thus, this mini-review aimed
to summarize and discuss previous and current data to provide an overview of the clinical
presentation, diagnosis, frequency, and therapeutic management of PDRNP.
METHODS
A review of published literature collected by searching the PubMed and Google-scholar
databases using appropriate search terms was performed.
RESULTS
In total, 18 articles dealing with the topic of interest were retrieved (Table 1).
Concerning the clinical presentation, patients with PDRNP may complain of motor, sensory,
or autonomic symptoms, which can be confirmed by appropriate clinical investigation,
autonomic testing, nerve conduction studies (NCSs), and nerve biopsy. In most patients,
NCSs revealed an axonal lesion of motor, sensory, or both sensory and motor fibers
(Table 1). Hereditary PDRNP is predominantly a large fiber neuropathy, whereas acquired
PDRNP manifests frequently as small fiber neuropathy (Table 1). Autonomic testing
may reveal cardiovascular autonomic neuropathy or impaired electrochemical skin conductance
(3). Thus far, nerve biopsy has not been carried out in patients with PDRNP; therefore,
we do not regard nerve biopsy as a cornerstone for diagnosing PDRNP (4) as it is only
applied if neuropathy (NP) due to vasculitis, sarcoidosis, amyloidosis, or leprosy
is suspected. Although small fiber neuropathy (SFN) can be difficult to diagnose (4),
the most sensitive method to detect SFN is skin biopsy (5).
Regarding its etiology, PDRNP is multicausal. It can present due to an underlying
genetic defect causing PD and NP, or it may be secondary due to side effects of treatment
or concomitant diseases in conjunction with NP (Table 1). Genetic disorders manifesting
with PD and NP include mitochondrial disorders (MIDs) (6), spino-cerebellar ataxias
(SCAs) (7), and hereditary spastic paraplegia (HSP) (8). An example of an MID manifesting
with PDRNP is multisystem MID due to mutations in POLG1 (Table 1) (6). Various mutations
in POLG1 that manifest phenotypically with PDRNP have been found (9). In addition
to POLG1 variants, mitochondrial PDRNP may also be due to mutations in C10orf12 (twinkle),
MPV17, and SLC25A46, or in mtDNA related genes (Table 1). An example of a HSP manifesting
with PDRNP is HSP39 due to mutations in PNPLA6 (8). An example of SCA manifesting
with PDRNP is SCA48 due to mutations in STUB1 (7).
PDRNP may also be caused by long-term usage of L-DOPA. L-DOPA may not only cause vitamin-B12
deficiency (L-DOPA induced vitamin-B12 deficiency), but also folate deficiency (10).
The notion that L-DOPA causes vitamin-B12 or folate deficiency, and thus secondary
PDRNP, has been challenged by findings from third world countries showing that low
vitamin-B12 and folate levels do not play a significant role in the development of
PDRNP (11). It has been increasingly recognized that levidopa/carbidopa intestinal
gel (LCIG) can be complicated by NP, particularly SFN (12,13). In a study of 33 patients
treated with LCIG, three patients developed symptomatic PDRNP and seven developed
subclinical PDRNP (13).
Diagnosis of NP relies on the history, clinical exam, blood tests, NCSs, electromyography
(EMG), and autonomic testing (4). EMG may serve as a supplementary method to explore
the effects of motor neuropathy on the skeletal muscles.
CONCLUSIONS
The etiologic spectrum of PDRNP is wider than anticipated, and genetic causes need
to be increasingly considered. Diabetes or anti-Parkinson medications should not be
readily considered as the most frequent cause of PDRNP to avoid overlooking genetic
causes, and a thorough genetic work-up should be implemented.