Neuronopathies

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Neuronopathy means the cell body is affected rather than the myelin or axon as in peripheral neuropathy. This article is focused on the sensory neuronopathies where there is primary degeneration of the dorsal root ganglion and trigeminal ganglion sensory neurons. It is a rare type of polyneuropathy.

Classification

The classification of neuropathic disorders is as follows

  • Neuronopathies (pure sensory or pure motor or autonomic)
    • Sensory neuronopathies (ganglionopathies)
    • Motor neuronopathies (motor neuron disease)
    • Autonomic neuropathies
  • Peripheral neuropathies (usually sensorimotor)
    • Myelinopathies
    • Axonopathies
      • Large- and small-fibre
      • Small-fibre

Anatomy

The dorsal root ganglion (DRG) contains the cell bodies of sensory pseudo-unipolar neurons. The dorsal roots contain their efferent projections. Capillaries supply the DRG and in doing so cause fenestration and thereby loosening the blood-nerve barrier. This increases susceptibility to antibodies and toxins.

There are two populations of neurons in the DRG. These are the large-light cells with their Aβ and Aδ fibre projections. The other population, which are the majority of the cells, are the small-dark cells and their unmyelinated C fibres. The afferent projections of the larger neurons containing proprioceptive and tactile sensation traverse the posterior column.

Epidemiology

It is more common in women. The median age of onset is 54. Common comorbidities include diabetes, excessive alcohol intake, smoker, malignancy, autoimmune disease.[1]

Clinical Features

As the clinical features span multiple different specialties, when reading the literature it is important to keep in mind the "silo" effect. For example the neurology literature may under-report vestibular findings.

The sensory neuronopathies classically initially (but not always initially[1]) present with early onset sensory ataxia, potentially secondary to proximal muscle spindle and joint denervation.[2] This reflects damage to the large-fibre neurons. Note, early onset sensory ataxia is not unique to sensory ganglionopathy. It can also be caused by demyelinating large fibre neuropathy and pathology localised to the dorsal column. With severe proprioceptive loss the patient may have "pseudoathetosis" of the fingers and toes. If sensory ataxia doesn't present initially, it typically eventually manifests at full development.[1] It can also be subclinical. The sensory ataxia is eventually the main cause of disability. Most patients will have difficulty with tandem gait.

If the small and medium sized nerves are also involved then the patient may experience neuropathic pain (positive sensory symptoms). Positive features may include hyperaesthesia and allodynia.[2]

This leads to the other classic feature being that the negative symptoms (numbness) and positive symptoms often present with a non-length-dependent and multifocal pattern. This differentiates them from typical length dependent axonal sensory polyneuropathies. Misdiagnosis can occur if the examiner is testing sensation from distal to proximal and stops at the presumed sensory level, thereby missing the multifocal presentation. With severe diffuse involvement of DRGs the clinical pattern may mimic a length-dependent distribution.[1][3]

Symptoms can initially affect the upper limbs, lower limbs, or all four limbs. Symptoms can be asymmetrical or symmetrical. [1]

Vestibular dysfunction can occur, such as in CANVAS syndrome. CANVAS patients are also more likely to have chronic neurogenic cough, which can help distinguish this group. Vestibular dysfunction may be subclinical.

Power is usually normal, but patients may appear weak due to lack of proprioceptive feedback and loss of sensory input from denervated spindles and Golgi tendon organs.

The muscle stretch reflexes are often unelicitable.

Table 1. Clinical features[1]
Symptoms in % (n=53) At onset At full development At any time
Pain 17 (32) 32 (59)
Hypoaesthesia 36 (68) 53 (99)
Paraesthesia 27 (51) 24 (44)
Ataxia 17 (32) 51 (94)
Pseudoaethosis 0 (0) 12 (22)
Dry eyes and mouth 4 (7) 11 (20)
Autonomic symptoms 10 (19) 14/52 (27)
Orthostatic hypotension 4 (7) 6 (11)
Gastrointestinal dysfunction 4 (7) 8 (15)
Dysphagia 2 (4) 5 (9)
Erectile dysfunction 1 (2) 2 (4)
Bladder dysfunction 0 (0) 5 (9)
Sweating dysfunction 1 (2) 4 (7)
Pupil abnormalities 1 (2) 3/53 (6)
Vestibular dysfunction 5 (9)
Cough 6/53 (11)
Facial involvement 11 (20) 15 (28)
Motor involvement 15 (28)
Eye movement abnormalities 8 (15)
Generalised areflexia 28/52 (54)


Aetiology

  • Immune mediated disease: Sjogren syndrome, systemic lupus erythematosus, autoimmune hepatitis, celiac disease
  • Paraneoplastic disease: Small-cell lung cancer, bronchial carcinoma, breast cancer, ovarian cancer, Hodgkin lymphoma, transitional cell bladder cancer, prostate cancer, malignant mixed M€ullerian tumor, neuroendocrine tumor, sarcoma
  • Viral infections: HIV, EBV, VZV, HTLV-1
  • Vitamin B6
  • Intoxication
  • Neurotoxic drugs: pyridoxine, cisplatin, carboplatin, oxaliplatin
  • Hereditary and degenerative disorders: hereditary sensory autonomic neuropathy (HSAN), Charcot-Marie-tooth disease type 2B (CMT2B), sensory ataxia neuropathy with dysarthria and ophthalmoparesis (SANDO), facial-onset sensory motor neuronopathy (FOSMN), and Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS)[2]
  • Idiopathic

In a seminal 2021 paper, 225 patients with previously diagnosed chronic idiopathic axonal polyneuropathy were re-assessed. 34% of these patients had biallelic RFC1 expansions, and hence actually a neuronopathy (CANVAS syndrome). Of these patients 42% had isolated sensory neuropathy or sensory neuropathy with chronic cough. Vestibular and/or cerebellar involvement was often subclinical, identified in 58%. One quarter of patients with CANVAS syndrome had been previously diagnosed with other conditions.[3]

Investigations

The first step is usually nerve conduction studies. This is to identify severely reduced or absent SNAPs indicating severe, generalised, non-length-dependent sensory neuropathy. Upper extremity sensory nerves may be affected to a greater degree than lower extremity, unlikely axonal neuropathies.

MRI findings of T2 hyperintensity of the dorsal column is strongly supportive of the diagnosis. The dorsal column contains the central afferent projections of the DRG. This finding is not present in the majority of patients.[1]

Nerve ultrasound has been studied in patients with CANVAS syndrome.[4] Increased peripheral nerve diameter is seen in a neuronopathy process. Reduced or normal size is seen in a peripheral neuropathy process.

Diagnostic algorithm from 2016 Continuum article[5]

Resources

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Sancho Saldaña, Agustin; Mahdi‐Rogers, Mohamed; Hadden, Robert David (2021-03). "Sensory neuronopathies: A case series and literature review". Journal of the Peripheral Nervous System (in English). 26 (1): 66–74. doi:10.1111/jns.12433. ISSN 1085-9489. Check date values in: |date= (help)
  2. 2.0 2.1 2.2 Gwathmey, Kelly Graham (2016-01). "Sensory neuronopathies". Muscle & Nerve. 53 (1): 8–19. doi:10.1002/mus.24943. ISSN 1097-4598. PMID 26467754. Check date values in: |date= (help)
  3. 3.0 3.1 Currò, Riccardo; Salvalaggio, Alessandro; Tozza, Stefano; Gemelli, Chiara; Dominik, Natalia; Galassi Deforie, Valentina; Magrinelli, Francesca; Castellani, Francesca; Vegezzi, Elisa; Businaro, Pietro; Callegari, Ilaria (2021-06-22). "RFC1 expansions are a common cause of idiopathic sensory neuropathy". Brain: A Journal of Neurology. 144 (5): 1542–1550. doi:10.1093/brain/awab072. ISSN 1460-2156. PMC 8262986. PMID 33969391.
  4. Pelosi, L.; Mulroy, E.; Leadbetter, R.; Kilfoyle, D.; Chancellor, A. M.; Mossman, S.; Wing, L.; Wu, T. Y.; Roxburgh, R. H. (2018-04). "Peripheral nerves are pathologically small in cerebellar ataxia neuropathy vestibular areflexia syndrome: a controlled ultrasound study". European Journal of Neurology. 25 (4): 659–665. doi:10.1111/ene.13563. ISSN 1468-1331. PMID 29316033. Check date values in: |date= (help)
  5. Gwathmey, Kelly Graham (2017-10). "Sensory Polyneuropathies". CONTINUUM: Lifelong Learning in Neurology (in English). 23 (5): 1411–1436. doi:10.1212/CON.0000000000000518. ISSN 1538-6899. Check date values in: |date= (help)