MEDICAL PROGRESS IN THE JOURNAL OF NEUROLOGY

Progress in peripheral nerve disease research in the last two years

Matthew Evans • Hadi Manji

Received: 12 September 2013 / Accepted: 16 September 2013 / Published online: 25 October 2013

� Springer-Verlag Berlin Heidelberg 2013

Abstract Peripheral nerve disorders have been a Cin-

derella subspecialty for neurologists because of the limited

treatment options and difficulties in obtaining a genetic

diagnosis. In the last decade, there has been great progress

in the management of patients with peripheral nerve dis-

ease. In this paper, we review a selection of diagnostic and

therapeutic papers in this area published in the Journal of

Neurology over the last 24 months.

Keywords Hereditary sensory and autonomic

neuropathy �Rituximab �Anti-MAG antibody disease �MRI

Genetic advances

The hereditary sensory and autonomic neuropathies

(HSAN) are a genetically diverse group of peripheral nerve

diseases. The clinical spectrum is wide, but is unified by

the common finding of a progressive, sensory neuropathy

which when marked, may lead to severe complications

including unintentional self-injury, skin ulcers and osteo-

myelitis sometimes necessitating amputation. There is

variable autonomic involvement and sometimes quite dis-

abling motor deficits develop in certain subtypes later in

the disease course [1, 2, 5, 6]. The classification of HSAN

has been strengthened by the discovery of twelve genes

since 2001, although these still account for less than 20 %

of cases [1, 2].

To further study the phenotype–genotype correlation

and the frequency of mutations in these known genes,

Davidson et al. [1] screened 140 patients, with a clinical

picture consistent with HSAN, for mutations in the coding

regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B,

NTRK1 and NGFB. Four genes described following

completion of the study were clearly not screened. KAP

and CCT5 were not screened given that none of the 140

patients had the appropriate phenotype. A total of 25

patients with sequence variants in the coding regions of

the six screened genes were found. At least twenty of

these mutations were thought to be pathogenic, amounting

to 14.3 % of patients screened, not dissimilar to the 19 %

found in a European cohort of 100 patients [2]. Of these

mutations, the most frequent, found in thirteen British

Caucasian patients, was the common p.Cys133Trp muta-

tion in the SPTLC1 gene; a mutation first described in

2001 [3, 4]. Haplotype analysis in multiple affected

individuals with the p.Cys133Trp mutation has shown a

common haplotype across the SPTLC1 gene, strongly

suggesting a founder effect [5]. It is noteworthy that the

most common mutations in the European cohort were

found in RAB7, reflecting a different founder effect in that

group [6]. In contrast, RAB7 mutation was detected in

only one family in the current study.

In the UK, p.Cys133Trp is the most common mutation

and causes autosomal dominant HSAN1 [5]. The authors

report that patients with this mutation presented with the

typical HSAN1 phenotype: mostly becoming symptomatic

in the second or third decades with decreased sensation in

the feet, often associated with lancinating pain and par-

aesthesia. Painless ulcers were found in all families, with

Charcot joints and amputations in some patients. There

can be marked variation in phenotype, an example of

which is a severe congenital HSAN1 phenotype described

M. Evans (&) � H. Manji

The MRC Centre for Neuromuscular Diseases, The National

Hospital for Neurology and Neurosurgery, Queen Square,

London WC1N 3BG, UK

e-mail: matthew.evans@ucl.ac.uk

123

J Neurol (2013) 260:3188–3192

DOI 10.1007/s00415-013-7121-x

in a patient with a novel SPTLC1 mutation (c.992C [ T;

p.Ser331Phe) [6].

The next most common mutation in this group was in

the NTRK1 gene, in which four pathogenic variants,

including two novel variants, were found. Mutations in

NTRK1 cause HSAN4, an autosomal recessive form of

HSAN also known as congenital insensitivity to pain with

anhidrosis (CIPA). Mutations in this gene included two

homozygous nonsense and one homozygous missense

mutations in three patients from different Saudi Arabian

families, each with consanguineous heterozygous parents.

Each of these patients had symptoms at birth and was

affected by CIPA, resulting in injury to lips/tongue and

osteomyelitis, without motor involvement and normal

reflexes. Two had cognitive delay. This phenotype is in

keeping with that previously reported for this mutation. A

novel homozygous missense mutation (p.Glu492Lys)

resulting in a congenital syndrome consisting of sensory

neuropathy, anhidrosis, seizures, deafness and develop-

mental delay was also found.

Other mutations, including several novel ones, were rare

in this study. In two Maltese patients, novel frameshift

mutations in WNK1/HSN2 were found, resulting in an

autosomal recessive congenital syndrome of CIP and ul-

ceromutilative complications. A previously reported

homozygous nonsense mutation in FAM134B (p.Gln145X)

was also found in a patient with HSAN2. Finally, a het-

erozygous duplication was found in the NGFB gene in a

British female presenting in her late 40 s with a progressive

sensory neuropathy.

To date, it has been shown in vitro, that mutations in

SPTLC1 lead to alteration in function of the enzyme serine

palmitoyltransferase resulting in production and accumu-

lation of the neurotoxic sphingolipid metabolites 1-deox-

ysphinganine and 1-deoxymethylsphinganine [7, 8]. A trial

in 14 patients with HSAN1 showed that low dose oral

L-serine lowered deoxysphingolipid levels, with some

patients reporting improvement in distal sensation [9],

though the latter was not examined objectively.

Based on this study, the authors have developed an

algorithm for genetic testing of patients with HSAN in the

UK, but note that many more HSAN genes are yet to be

discovered. As more is discovered about the genetic basis

of HSAN, and the precise mechanisms by which each of

these mutations results in neuropathy, we move ever closer

toward targeted therapies.

Rituximab in the treatment of peripheral nerve disease

Rituximab is a chimeric IgG1 monoclonal antibody direc-

ted against the B-lymphocyte surface antigen CD-20.

Licensed for use in the treatment of certain immune-

mediated haematological diseases and in rheumatoid

arthritis, it has also been shown to have efficacy in the

treatment of paraproteinaemic neuropathies, including

polyneuropathy with antibodies directed against myelin-

associated glycoprotein (MAG), one study showing benefit

lasting up to 2 years in 80 % of patients [10].

In the first randomised-controlled trial, Dalakas et al.

[11] randomised 26 patients to four weekly infusions of

rituximab or placebo. After 8 months, four out of 13

patients treated with rituximab had an improved inflam-

matory neuropathy cause and treatment (INCAT) leg dis-

ability score compared with zero improving in the placebo

group. This became significant when a patient with normal

INCAT leg disability score at entry was excluded from the

analysis. At 8 months, IgM was reduced by 34 % and anti-

MAG titres by 50 % in the rituximab treated group.

Greatest improvement was seen in those with high anti-

MAG titres and severe sensory deficits at baseline. Leger

et al. [12] enrolled 54 patients with IgM anti-MAG

demyelinating neuropathy in a randomised, double-blind,

placebo-controlled trial, finding rituximab ineffective in

improving the primary outcome measure of mean change

in INCAT sensory score (ISS) at 12 months. There were

however improvements in several secondary outcome

measures at 12 months, including improvement of at least

two points in INCAT disability score, the self-evaluation

scale and two subscores of the Short Form-36

questionnaire.

Delmont et al. [13] looked further at the efficacy and

safety of rituximab in six patients with anti-MAG antibody

disease who received four weekly infusions of rituximab

over 9 months. Each patient underwent detailed clinical

evaluation with ISS, MRC score and overall neuropathy

limitation scale (ONLS) [14] before and three monthly

during treatment. Anti-MAG titre and CD-19 expressing B

cell count were also measured at these times. Nerve con-

duction studies were performed before treatment and

9 months following the last treatment (M9). Treatment was

considered effective only if ONLS decreased by at least

one point at M9. At M9, ONLS score improved by one

point in two patients, by two points in one, and remained

stable in the three others. ISS improved in five patients

(mean 3.8 points); MRC score improved in three patients

(mean 2.7 points). Anti-MAG titre decreased in all patients

at 9 months post treatment by a mean of 43 %. IgM

monoclonal titers decreased in five patients but did not

change in one. As expected, CD-19 B cell count fell dra-

matically after treatment and stayed low at 9 months.

There was no change in individual or overall electrophys-

iological data with treatment. No serious adverse events

were reported during the follow up period. The authors

conclude that treatment with rituximab is safe and

improves sensory deficit more than functional disability.

J Neurol (2013) 260:3188–3192 3189

123

No predictive factors of response to rituximab treatment

were identified.

Given that patients with anti-MAG antibody disease will

likely require long-term treatment over many years, bene-

fits of treatment with rituximab must be carefully weighed

against risks of sometimes potentially fatal side effects, the

most serious of which is progressive multifocal leukoen-

cephalopathy (PML), which has been reported in patients

with autoimmune disease receiving rituximab either con-

currently with or having previously received other immu-

nosuppressive therapy [15]. The risk of PML in patients

treated with rituximab alone needs further study.

The two largest randomised-controlled trials have yiel-

ded conflicting results, and therefore the jury is still out on

the use of rituximab in anti-MAG neuropathies. Both

prognostic factors and long-term effects are yet to be

clearly elucidated. For example, the predictive value of

anti-MAG antibody titres is not clear, with consistent

reduction in titre with treatment not correlating consistently

with clinical improvement, suggesting it is only one aspect

of pathogenesis. Results from further large studies are

awaited.

Standard initial therapy for c-ANCA positive vasculitis

has for many years been the combination of high dose

glucocorticosteroids and cyclophosphamide, a combination

which induces remission in the vast majority of patients at

6 months [16]. Given the cumulative dose-related toxicity

of cyclophosphamide, once remission is achieved a main-

tenance drug—usually azathioprine [16], is added. Two

randomised controlled trials: RAVE [17] and RITUXVAS

[18], suggest that rituximab is as effective as cyclophos-

phamide in inducing remission in patients with Wegener’s

granulomatosis/microscopic polyangiitis or for relapse of

disease following conventional treatments.

But what about treatment in patients who can’t tolerate

the usual induction therapy or for whom it is not

appropriate?

Although case reports may be criticised, nevertheless

they are useful in clinical practice and may lead to more

extensive research. Witsch et al. [19] describe a 70-year-

old female with recent recurrent upper respiratory tract

infections presenting with a subacute, symmetric sensori-

motor polyneuropathy resulting in quadriparesis and dia-

phragmatic involvement leading to intubation and

ventilation. cANCA was positive and further investigations

including nerve conduction studies, lumbar puncture and

MRI brain pointed to a diagnosis of Wegener’s granulo-

matosis with associated vasculitic polyneuropathy and

central nervous system involvement. Sural nerve, skin and

nasopharyngeal mucosa biopsies confirmed this diagnosis.

High dose steroids, plasmapheresis and intravenous

immunoglobulin were given with no neurological

improvement. The patient suffered lower gastro-intestinal

bleeding necessitating ileocaecal resection complicated by

peritonitis and poor wound healing. Considering these

complications and the lack of neurological improvement,

rituximab was chosen in place of standard treatment with

cyclophosphamide and steroids, resulting in neurological

improvement with no detrimental effect on wound healing

and peritonitis.

The authors thus demonstrate the efficacy of rituximab

as a useful alternative to standard treatment without

impairment of wound healing or exacerbation of local

infection, providing further support for the two randomised

controlled trials mentioned above [17, 18].

Imaging peripheral nerves

Magnetic resonance imaging (MRI) has relatively recently

been added to the diagnostic armamentarium of the neu-

romuscular specialist. Supplementing the history, clinical

and electrophysiological examination, MRI aids diagnosis

and management of peripheral nerve disease by enabling

precise localisation and detailed characterisation of

peripheral nerve lesions, often in areas inaccessible to

standard electrophysiology. In future, it may also prove

beneficial in guiding the site of nerve biopsy, as is already

done in muscle disorders.

High signal in damaged nerve on T2-weighted (T2w)

sequences correlates well with abnormalities seen on elec-

trophysiological examination [20, 21]. Furthermore,

denervated muscle can be visualised, helping further in

diagnosis and indicating extent of neural involvement.

Denervated muscle appears high in signal on T2w imaging

acutely, most likely reflecting increased extracellular mus-

cle water [22–24]. With time, this T2w high signal

decreases and may be replaced by increased signal on T1-

weighted (T1w) imaging, reflecting potentially irreversible

fatty infiltration. Addition of techniques for suppression of

signal from all non-neural structures as well as other tech-

niques such as diffusion tensor imaging has added signifi-

cantly to the applicability and utility of nerve MRI.

Berciano et al. [25] reported on their serial electro-

physiological and MRI findings in a 74-year-old man with

acute motor axonal neuropathy (AMAN). The patient

presented with symmetric, flaccid lower limb weakness

progressing to near complete tetraplegia and areflexia over

several days. CSF was normal. Antiganglioside profile was

characteristic of AMAN. Electrophysiology showed find-

ings consistent with AMAN with absent or severely

reduced CMAP with motor nerve conduction velocities

preserved or only mildly slowed where obtainable. There

was active denervation in foot and lower leg muscles, as

well as in thigh muscles to a lesser degree. He was treated

with a standard course of intravenous immunoglobulin;

3190 J Neurol (2013) 260:3188–3192

123

1 month later he was able to walk supported and by 2 years

was independent in mobility albeit with distal wasting in all

limbs, and severe weakness of ankle and toe dorsiflexion.

Five serial lower limb 1.5-T MRI scans were performed

over a period of 2 years beginning 1 month following

admission. Hyperintensity on T2w fat suppressed (T2FS)

images was apparent at 2 months in all calf muscles and to

a lesser degree in thigh muscles, though T1w imaging

remained normal. Hyperintensity on T2-weighted images

was further increased at 6 months. These changes corre-

lated well with electromyography findings of widespread

active denervation in EDB, TA and quadriceps muscles.

Complete clinical recovery in thigh muscles correlated well

with resolution of T2FS hyperintensity at 2 years, whereas

subtle increased signal on T1w imaging correlated well

with residual distal wasting and severe weakness of ankle

and toe dorsiflexion.

The authors support the use of MRI as a useful adjunct

to neurophysiology for diagnosis and prognostication in

patients with AMAN, particularly useful in its ability to

draw information from the significant number of muscles

inaccessible to standard neurophysiology. They note that

further studies with larger numbers of patients are needed

to optimise the timing of MRI.

Sciatic nerve injury is a recognised complication of

gluteal intramuscular injection from which complete

recovery is unfortunately not the rule [26]. With current

techniques, prognostication remains difficult. MRI is able

to precisely detect peripheral nerve injury [27], with high

signal on T2w imaging in the damaged nerve and dener-

vated muscles detected early [28]. One group has shown

that resolution of this MR signal abnormality predicts

axonal regeneration prior to clinical improvement, and

before reinnervation is seen on electromyography [29],

while lack of resolution predicts persistent damage there-

fore portending a poor prognosis [29–31].

In their case series, Pham et al. [29] examined the use of

MR neurography (MRN) as a supplementary diagnostic

tool in iatrogenic sciatic nerve injection injury, assessing

whether MRN could provide objective evidence for sciatic

injection injury and whether it could predict the severity

and extent of injury. At variable time points following

injection injury, three patients with varying severities of

sciatic nerve injury underwent serial assessments including

neurological examination, electrophysiology and gluteal/

lower limb 1.5-T MRI: T1w and T1w contrast-enhanced

sequences to precisely identify the neural anatomy/vascu-

lature and T2w with fat suppression (STIR) to identify the

site and severity of nerve injury. In two patients with

clinically severe sciatic nerve injury, MRN correctly pre-

dicted severe, axonal sciatic lesions; high signal on T2w

sequences in nerve and muscle correlating well with nerve

conduction studies and spontaneous activity in appropriate

muscles on electromyography. In the third patient, MRN

was normal (as was electrophysiology), indicating no

axonal damage and correctly predicting full recovery at

2 weeks.

The authors show that MRN can precisely localise and

reveal the extent of injection-related axonal sciatic nerve

injury. They also note that MRN may be useful in follow

up and in prognostication, the latter given that regression of

high signal may precede both clinical and electrophysio-

logical improvement. Optimal timing of imaging remains a

question for further study.

Conflicts of interest None.

References

1. Davidson G et al (2012) Frequency of mutations in the genes

associated with hereditary sensory and autonomic neuropathy in a

UK cohort. J Neurol 259(8):1673–1685

2. Rotthier A et al (2012) Mechanisms of disease in hereditary

sensory and autonomic neuropathies. Nature reviews. Neurology

8(2):73–85

3. Dawkins JL et al (2001) Mutations in SPTLC1, encoding serine

palmitoyltransferase, long chain base subunit-1, cause hereditary

sensory neuropathy type I. Nat Genet 27(3):309–312

4. Bejaoui K et al (2001) SPTLC1 is mutated in hereditary sensory

neuropathy, type 1. Nat Genet 27(3):261–262

5. Houlden H et al (2006) Clinical, pathological and genetic char-

acterization of hereditary sensory and autonomic neuropathy type

1 (HSAN I). Brain: J Neurol 129(Pt 2):411–425

6. Rotthier A et al (2009) Genes for hereditary sensory and auto-

nomic neuropathies: a genotype-phenotype correlation. Brain: J

Neurol 132(Pt 10):2699–2711

7. Eichler FS et al (2009) Overexpression of the wild-type SPT1

subunit lowers desoxysphingolipid levels and rescues the phe-

notype of HSAN1. J Neurosci 29(46):14646–14651

8. Penno A et al (2010) Hereditary sensory neuropathy type 1 is

caused by the accumulation of two neurotoxic sphingolipids.

J Biol Chem 285(15):11178–11187

9. Garofalo K et al (2011) Oral L-serine supplementation reduces

production of neurotoxic deoxysphingolipids in mice and humans

with hereditary sensory autonomic neuropathy type 1. J Clin

Investig 121(12):4735–4745

10. Benedetti L et al (2007) Predictors of response to rituximab in

patients with neuropathy and anti-myelin associated glycoprotein

immunoglobulin M. J Peripher Nerv Syst JPNS 12(2):102–107

11. Dalakas MC et al (2009) Placebo-controlled trial of rituximab in

IgM anti-myelin-associated glycoprotein antibody demyelinating

neuropathy. Ann Neurol 65(3):286–293

12. Leger JM et al (2013) Placebo-controlled trial of rituximab in

IgM anti-myelin-associated glycoprotein neuropathy. Neurology

80(24):2217–2225

13. Delmont E et al (2011) Treatment with rituximab in patients with

polyneuropathy with anti-MAG antibodies. J Neurol 258(9):

1717–1719

14. Graham RC, Hughes RA (2006) A modified peripheral neurop-

athy scale: the overall neuropathy limitations scale. J Neurol

Neurosurg Psychiatry 77(8):973–976

15. Molloy ES, Calabrese LH (2012) Progressive multifocal leuko-

encephalopathy associated with immunosuppressive therapy in

rheumatic diseases: evolving role of biologic therapies. Arthr

Rheum 64(9):3043–3051

J Neurol (2013) 260:3188–3192 3191

123

16. Jayne D et al (2003) A randomized trial of maintenance therapy

for vasculitis associated with antineutrophil cytoplasmic autoan-

tibodies. New Engl J Med 349(1):36–44

17. Stone JH et al (2010) Rituximab versus cyclophosphamide for

ANCA-associated vasculitis. New Engl J Med 363(3):221–232

18. Jones RB et al (2010) Rituximab versus cyclophosphamide in

ANCA-associated renal vasculitis. New Engl J Med

363(3):211–220

19. Witsch J et al (2011) Rituximab in c-ANCA associated vasculitic

polyneuropathy complicated by local peritonitis. J Neurol

258(12):2281–2283

20. Gupta R, Villablanca PJ, Jones NF (2001) Evaluation of an acute

nerve compression injury with magnetic resonance neurography.

J Hand Surg 26(6):1093–1099

21. Kim S et al (2007) Role of magnetic resonance imaging in

entrapment and compressive neuropathy—what, where, and how

to see the peripheral nerves on the musculoskeletal magnetic

resonance image: part 1. Overview and lower extremity. Eur

Radiol 17(1):139–149

22. Kamath S et al (2008) MRI appearance of muscle denervation.

Skelet Radiol 37(5):397–404

23. Bendszus M et al (2002) Sequential MR imaging of denervated

muscle: experimental study. AJNR Am J Neuroradiol 23(8):

1427–1431

24. Polak JF, Jolesz FA, Adams DF (1988) Magnetic resonance

imaging of skeletal muscle. Prolongation of T1 and T2 sub-

sequent to denervation. Investig Radiol 23(5):365-369

25. Berciano J et al (2012) Magnetic resonance imaging of lower

limb musculature in acute motor axonal neuropathy. J Neurol

259(6):1111–1116

26. Kline DG et al (1998) Management and results of sciatic nerve

injuries: a 24-year experience. J Neurosurg 89(1):13–23

27. Stoll G et al (2009) Magnetic resonance imaging of the peripheral

nervous system. J Neurol 256(7):1043–1051

28. Bendszus M, Stoll G (2005) Technology insight: visualizing

peripheral nerve injury using MRI. Nature clinical practice.

Neurology 1(1):45–53

29. Pham M et al (2011) MR neurography of sciatic nerve injection

injury. J Neurol 258(6):1120–1125

30. Wessig C et al (2004) Muscle magnetic resonance imaging of

denervation and reinnervation: correlation with electrophysiology

and histology. Exp Neurol 185(2):254–261

31. Bendszus M et al (2004) MRI of peripheral nerve degeneration

and regeneration: correlation with electrophysiology and histol-

ogy. Exp Neurol 188(1): 171-177

3192 J Neurol (2013) 260:3188–3192

123