1 APRIL 2022 ausdoc . com . au nerve fibres predominantly affected ( large or small fibre neuropathies ).
It is important to note that the types and subclassifications are not mutually exclusive and serve mainly to limit the differential diagnostic considerations . 8
The importance of determining the type of neuropathy is illustrated by the common condition , distal sensory poly neuropathy ; if this is found to be an axonopathy , the patient can be reassured of the unlikelihood of progression to non-ambulation . 9 , 10
Table 2 outlines the types of neuropathies and nerve fibres affected .
Axonal polyneuropathies
The most commonly encountered type is a symmetrical , axonal and length-dependent pattern . The health and functioning of peripheral nerves depend on the integrity and effectiveness of the bidirectional axonal transport between cell body ( the anterior horn cells , dorsal root ganglia ) and the neuromuscular junction . This , in turn , depends on the kinesin and dynein – dynactin families of transport proteins . Toxins and pathologies affect these proteins , and the resultant disruption of axonal transport leads to distal axonal degeneration with consequent length-dependent dying back , or Wallerian degeneration of the axons ( see figure 1 ). This is a common pathophysiological mechanism underlying toxic or metabolic neuropathies . 11
There are multiple diagnostic possibilities with axonal polyneuropathies . Differential diagnoses can be shortlisted based on history , especially the evolution of symptoms and pattern of affliction ( sensory / motor predominant and mixed ), examination , systemic features and tailored evaluation .
Demyelinating polyneuropathies
Effective nerve conduction is contingent on the integrity of myelin that allows saltatory conduction across the nerve fibre . Demyelinating neuropathies impair nerve conduction by impeding the propagation of action potentials along nerve fibres .
Acquired demyelinating neuropathies are mostly immune-mediated and follow molecular mimicry to antigenic targets in the paranodal or juxtaparanodal regions of the internode .
12 , 13
The clinical presentation varies depending on the type of antigen target and the autoantibodies generated . 14-16 These include motor neuropathies , sensory ataxic neuropathies and Miller Fisher syndrome of cranial nerve involvement .
As the blood-nerve barrier is less impervious at the dorsal root ganglia , nerve roots and terminal nerve endings , these regions are preferentially involved in the immune polyradiculoneuropathies . Except for myelin-associated glycoprotein ( MAG ), there is little or no overlap between the molecular targets of acquired immune neuropathies and hereditary
17 , 18 neuropathy .
Large fibre neuropathies
Patients with these neuropathies describe numbness or loss of sensation . Sometimes the only sign of motor involvement is wasting of the intrinsic / small muscles of the foot ; weakness of these small muscles may go undetected by both the patient and practitioner .
Small fibre neuropathies
Patients with small fibre neuropathies often present with painful
Table 2 . Nerve fibre types and neuropathies Type of neuropathy Clinical manifestation Diagnostics Comments
Large fibre neuropathy ( affects Aα , Aβ , Aδ fibres , 1-20 µ m in diameter )
Small fibre neuropathy ( affects C fibres , 0.2-1.5 µ m in diameter )
Axonal neuropathy ( Wallerian degeneration of axons )
Demyelinating neuropathy ( degeneration of myelin sheath with relative preservation of nerve axon )
© 2014 Poornima Ramburrun et al / CC BY / bit . ly / 3BllkHn
Figure 1 . Wallerian degeneration .
dysaesthesias such as burning or shooting pains with or without accompanying autonomic symptoms . By definition , a pure small fibre neuropathy has normal large fibre sensation ( touch , pressure , proprioception ), strength and muscle stretch reflexes , and normal routine nerve conduction studies . That said , patients with small fibre neuropathy may have concomitant large fibre involvement .
Tingling , numbness , proprioceptive ataxia
Atypical patterns
Consider hereditary motor neuropathies and distal myopathies in patients with a slowly progressive motor predominant length-dependent pattern . Sparing of toe extension relative to foot dorsiflexion may suggest myopathy as a cause of symmetric footdrop .
Sensory symptoms in the hands that precede the onset of lower limb symptoms ( especially progression beyond knee level ) is atypical of a length-dependent axonal neuropathy and rules out a demyelinating neuropathy .
Consider a sensory neuropathy in atypical patchy loss of sensation over
Burning sensation , autonomic symptoms
Length-dependent evolution Deep tendon reflexes ( DTRs ) relatively preserved until severe weakness
Non-length-dependent evolution , affecting non-contiguous regions sequentially or simultaneously
DTRs lost early and disproportionate to weakness
Neurophysiological testing reveals the extent of severity
Routine evaluation including neurophysiology usually unremarkable
Reduced compound muscle action potential ( CMAP ) amplitude with relatively preserved velocities of nerve conduction
Prolonged nerve conduction latencies with reduced velocity of conduction and at times conduction blocks with relatively preserved amplitude of action potential
Raised CSF protein
the trunk , upper limbs or scalp in an otherwise length-dependent pattern of evolution .
In patients with upper limb symptoms , consider the possibility of cervical myelopathy and carpal tunnel syndrome . 8
CLINICAL APPROACH
SYMPTOMS of neuropathy developing in specific patterns help identify the type and allow for diagnostic workup and treatment . Also consider the patient ’ s perception of their ailment and their expected outcome .
Investigation
A non-length-dependent or patchy pattern of evolution warrants rapid and extensive evaluation , given these raise the possibility of immune demyelinating polyneuropathies that are often amenable to disease-modifying therapies . 19
Avoid electrodiagnostic testing in those with long-standing symptoms with minimal deficits , unless the results of testing are likely to affect
20 , 21 management .
Common presentation in metabolic and nutritional deficiency neuropathies
Punch skin biopsy for intra-epidermal nerve fibre density
Commonly metabolic and toxic aetiology although immune and inflammatory types also exist
Warrants excluding immune and inflammatory causes that are potentially treatable and at times life-threatening , such as Guillain-Barré syndrome ( GBS )
The American Academy of Neurology guidelines recommend ordering blood glucose , vitamin B12 , methylmalonic acid and serum protein immunofixation in patients with distal symmetric polyneuropathy patterns . 22 Consider referring for CSF analysis with a polyradiculopathy or polyradiculoneuropathy pattern . 22
Around 10 % of patients with diabetes and neuropathy are likely to have an alternative or additional cause for their neuropathy . 23 Fasting blood glucose and HbA1c are common screening tools . A two-hour glucose tolerance test ( GTT ) is more sensitive at detecting glucose intolerance in its early stage . This can be particularly valuable in patients with small fibre neuropathy where diagnostic yield is much lower compared with neuropathies with predominantly large fibre involvement ( that is , a GTT will more accurately diagnose impaired glucose tolerance in patients with small fibre neuropathy than will a fasting blood glucose and
HbA1c ). 24
Genetic testing can allow for diagnosis and , at times , disease-specific intervention ( for example , Fabry disease ). 25
Nerve biopsy is reserved as the final evaluation of neuropathies because of the invasive nature and low diagnostic yield . However , skin biopsy may be the only specific diagnostic test for small fibre neuropathy ; intraepidermal nerve fibre density measurements have a sensitivity of 90 %, specificity of 95 % and negative predictive value of 91 %. 26
TREATMENT OF NEUROPATHIC PAIN
START with an assessment of the patient ’ s expectations and set realistic goals . A 2001 study compared the pain intensity numerical rating scale ( PI-NRS ) and patient global impression of change ( PGIC ) seeking to evaluate the “ clinically important differences in pain intensity scales used for chronic pain studies ”. They noted that “ a reduction of approximately 30 % in the PI-NRS represented a clinically important difference ”. 27
It is vital to treat comorbid depression and anxiety ; these can affect the perception of pain and subjective response to therapy , and treatment improves overall quality of life . A multidisciplinary approach is preferred over neuro-pharmacotherapy alone .
Before initiating drugs for the treatment of neuropathic pain , discuss the concept of ceiling dose ( see table 3 ) and duration of adequate therapy . This enables informed , active patient participation and improves compliance in what can be a long process with obscure milestones .
The treatment of neuropathic pain is often not adequate and beset by infrequent use and / or underdosing of treatments that have proven efficacy . 28
Drugs commonly used to treat neuropathic pain ( see table 3 ) include tricyclic antidepressants ( amitriptyline , nortriptyline ), antiepileptic drugs ( pregabalin , gabapentin , carbamazepine ), SNRI antidepressants ( duloxetine , venlafaxine ) and topical agents ( lidocaine , capsaicin ).
DIABETIC NEUROPATHIES
DIABETES mellitus and prediabetes ( glucose intolerance ) are common causes of neuropathy ( see box 1 ). Up to 50 % of patients with diabetes may experience symptoms of peripheral neuropathy and many asymptomatic patients have neurophysiologic features of neuropathy on nerve conduction studies .
29 , 30
The yearly incidence of distal symmetric polyneuropathy in patients with diabetes is about 2 %, and the lifetime incidence of neuropathy is estimated to be 37-45 % for patients with type 2 diabetes and 54-59 % for those with type 1 diabetes . 31
Neuropathy is not only a late complication but can develop at the earliest stages of glucose dysregulation . Painful sensory neuropathy can be the only presenting symptom in an undiagnosed patient . For this reason , in suggestive clinical contexts , consider further testing with an oral glucose tolerance in patients with slightly elevated HbA1c or even a normal HbA1c . 32 Treatment-induced neuropathy may occur in patients with poorly controlled diabetes within weeks of rapid glycaemic control , and manifests with burning pain or autonomic dysfunction from small fibre affliction . 34
Differential diagnosis of diabetic neuropathies
Given the high prevalence of diabetes and the incidence of neuropathies in patients with diabetes , it is imperative to consider and exclude diabetic neuropathy to avoid overlooking other treatable causes of neuropathy ( such as immune-mediated and treatable causes of polyneuropathy ).
A retrospective study of patients with distal sensory polyneuropathy and diabetes found additional causes for neuropathy in 53 % of patients . 38 The common causes included neurotoxic medications , alcohol abuse , monoclonal gammopathy , vitamin B12 deficiency , and renal disease . Around 25 % of patients had more than one additional cause . The authors concluded that the patients with sensory symptoms in the hands are more likely to have an additional cause for their neuropathy . 38
Treatment of diabetic neuropathies
Although there are no definitive and disease-modifying treatments , the severity of diabetic neuropathy is amenable to modulation especially in the early stages of glucose intolerance . Management focuses on modulation of risk factors and glycaemic control . Glucose metabolism is adversely affected by thiazide diuretics , so avoid these in patients with diabetes .
Hyperlipidaemia is also implicated in the pathogenesis of diabetic