Neurological Sciences

, Volume 30, Issue 2, pp 149–151

Painful neuropathy in subclinical hypothyroidism: clinical and neuropathological recovery after hormone replacement therapy


    • Neuromuscular Diseases UnitNational Neurological Institute “Carlo Besta”
  • Raffaella Lombardi
    • Neuromuscular Diseases UnitNational Neurological Institute “Carlo Besta”
  • Francesca Camozzi
    • Neuromuscular Diseases UnitNational Neurological Institute “Carlo Besta”
  • Claudia Ciano
    • Neurophysiological UnitNational Neurological Institute “Carlo Besta”
  • Giuseppe Lauria
    • Neuromuscular Diseases UnitNational Neurological Institute “Carlo Besta”
Case Report

DOI: 10.1007/s10072-009-0026-x

Cite this article as:
Penza, P., Lombardi, R., Camozzi, F. et al. Neurol Sci (2009) 30: 149. doi:10.1007/s10072-009-0026-x


We describe a 60-year-old woman complaining of severe burning feet for 3 months. A neurological examination showed absent Achilles tendon reflexes; nerve conduction study demonstrated mild sensory neuropathy, and skin biopsy revealed a length-dependent loss of intraepidermal nerve fibres. Haematological exams demonstrated a subclinical hypothyroidism and hormone replacement therapy was started. Conversely, symptomatic treatments for neuropathic pain were withdrawn after few days because of side effects. During the following months, thyroid function recovered, and the patient experienced a progressive decrease of neuropathic pain intensity. At 6- and 12-month follow-ups, nerve conduction study and clinical examination were normal, whereas skin biopsy demonstrated a complete reinnervation of the epidermis. Subclinical hypothyroidism is a possible cause of sensory neuropathy and hormone replacement therapy can prompt nerve regeneration.


Painful neuropathyNerve regenerationSkin biopsyThyroidNerve conduction study


The prevalence of peripheral nerve disorders associated with hypothyroidism ranges between 10 and 70%. The clinical picture varies from entrapment mononeuropathy to sensorimotor polyneuropathy with neuropathic pain in a stocking-glove distribution. Patients can also complain of muscle and joint pain, cramps, fatigue, and weakness [1, 2]. Deposits of amino glycane matter surrounding nerves, segmental demyelination, and primary axonal degeneration have been proposed as mechanisms for peripheral nerve dysfunction in hypothyroidism, which physiopathology remains, however, unclear. Studies in animal models have shown that hypothyroidism can alter myelin sheath compaction, induce dysfunctions in the relationship between axons and oligodendroglia, and interfere with the expression of high molecular weight neurofilament in the central nervous system [3, 4]. Similar mechanisms may affect also the functions of peripheral nerves.

Hormone replacement treatment can ameliorate symptoms and improve nerve conduction parameters in some patients [1], although nerve regeneration has never been demonstrated in follow-up studies. We describe a patient with sensory neuropathy associated with hypothyroidism in whom hormone replacement treatment led to the regeneration of skin nerve fibres and the recovery of neuropathic pain.

Case report

A 60-year-old woman was referred to our institution because of shooting pain and burning in the feet for 3 months. The onset was subacute with severe night-time pain that interfered with sleep. After a few weeks, symptoms worsened involving the lower limbs up to the ankles and lasting over the daytime. The physical examination was normal and the heart rate was 68/min. The neurological examination was normal except for absent Achilles tendon reflexes. Superficial and proprioceptive sensations as well as muscle strength were unremarkable even at the distal site of the lower limbs. The intensity of pain was scored 8 at the 10 cm visual analogue scale (VAS).

Nerve conduction study demonstrated a mild sensory neuropathy characterised by decrease of sural nerve conduction velocity (NCV) and sensory nerve action potential (SNAP) amplitude (7.7 μV and 36.9 m/sec on the right side and 7.9 μV and 37 m/sec on the left side; normal value 10 μV and 42 m/sec; antidromic technique). Sensory nerve conduction study at the upper limbs was normal. Motor nerve conduction study and needle electromyography at upper and lower limbs were unremarkable. The patient underwent 3-mm punch skin biopsies at the proximal thigh (20 cm below the anterior iliac spine) and the distal leg (10 cm above the lateral malleolus), which showed a length-dependent small fibre neuropathy. Intra-epidermal nerve fibre (IENF) density was 9.5/mm at the proximal thigh and 3.7/mm at the distal leg (normal values 12.8 ± 0.035 (SE) and 7.6/mm ± 0.026 (SE), respectively [5]).

Haematological exams revealed subclinical hypothyroidism [TSH 13.92 μU/ml (normal value 0.27–4.2); FT3 2.4 pg/ml (normal value 1.8–4.6); FT4 9.3 pg/ml (normal value 9.3–17.0)]. Serum vitamin B12 and folate, oral glucose tolerance test, screening for anti-thyroid antibodies and immune-mediated systemic diseases, serum and urine immunofixation, and anti-sulfatide antibodies were negative. Thyroid echography demonstrated an overall reduction of the gland volume and a 4-mm diameter hypoechogen nodule in the right lobe. Needle biopsy was negative for malignancy. After endocrinological consultation, the patient was diagnosed with primary subclinical hypothyroidism and hormone replacement therapy was started. In the meanwhile, pregabalin (75 mg/day) was started as first-line treatment for neuropathic pain, but it was discontinued after only 1 week because of intolerable dizziness and daytime sleepiness. Amytriptiline (25 mg/day) was therefore started and withdrawn after a few days for similar side effects.

During the following weeks, hormone replacement therapy led to the normalisation of TSH value (FT3 4.3 pg/ml, FT4 12 pg/ml; TSH 2. μU/ml), while the patient experienced a progressive decrease of neuropathic pain intensity that, at 3-month follow-up, was scored 2 at VAS. After 6 months, she reported only transient and slight discomfort in the feet. The neurological examination was unchanged, whereas sural NCV and SNAP amplitude recovered (11.6 μV and 56 m/s on the right side and 9.5 μV and 50 m/s on the left side). Skin biopsies were performed close to scars of those formerly taken and revealed a significant improvement of IENF density at both proximal thigh (15.0/mm) and distal leg (6.7/mm) (Fig. 1). At 12-month follow-up, the patient did not complain of any sensory symptom and the neurological examination showed normal Achilles tendon reflexes. Further skin biopsies confirmed the recovery of neuropathy, with normal density of IENF at both proximal thigh (17.3/mm) and distal leg (8.9/mm).
Fig. 1

Skin biopsies taken at the distal leg before (a) and 6 months after (b) replacement hormone therapy. Arrows indicate IENF; arrowheads indicate dermal nerve bundles. Bright-field immunohistochemistry in 50-μm thick sections with polyclonal rabbit anti-protein-gene-product 9.5 antibody (Ultraclone, UK). Bar = 60 μm


Hypothyroidism is one of the most common endocrinal disorders, with a prevalence of 0.5–1% in the general population. It can cause a variety of signs and symptoms reflecting the involvement of central nervous system, peripheral nerves, and muscles. Entrapment neuropathies and myopathies are most frequently observed. Axonal sensorimotor polyneuropathy with predominant impairment of large myelinated fibres has been reported in about 40% of patients [2, 6], and painful small fibre neuropathies have been described [7].

Whether subclinical hypothyroidism can affect peripheral nerves remains uncertain. Axonal neuropathy has been described in patients with normal thyroid hormone level and increased serum TSH, or abnormal TSH level to TRH stimulation [8]. Nevertheless, other authors did not find peripheral nerve abnormalities in patients with similar hormone dysfunctions [9]. In our patient, the temporal relationship between the onset of neuropathy and the response to replacement hormone therapy is in favour of a pathogenetic correlation. In particular, the significant decrease in neuropathic pain severity, achieved without any analgesic treatment, paralleled the improvement of sensory nerve conduction and the regeneration of cutaneous nerves, reflecting the recovery both of large and small fibres. Previous authors reported that replacement hormone treatment can improve symptoms, and in some patients, also neurophysiological abnormalities in about 3 months [1, 6, 8, 10]. This is the first observation that it can even induce axonal regeneration.

The relationship between skin innervation density and neuropathic pain remains partly unaddressed. In painful neuropathies of different aetiology, including HIV and diabetes-related neuropathies, IENF density did not correlate with pain intensity, although patients with pain had a lower innervation density than those without pain [5, 11, 12]. Nevertheless, patients can experience a decrease of neuropathic pain intensity after skin nerve regeneration, as it has been reported in pre-diabetes [13] and steroid-responsive neuropathy [14]. Therefore, we can currently assume that the loss of IENF is associated with the risk of developing neuropathic pain, which intensity can decrease after skin reinnervation [15]. Skin biopsy, a reliable technique to detect early neuropathy and to monitor its progression, can be used therefore as an outcome measure to assess the response to neuroprotective treatments in peripheral neuropathies.

While neuropathic pain can severely affect the quality of life of patients, the efficacy of symptomatic treatments remains disappointing [16]. Detection of a possible aetiology for painful neuropathy allows starting an appropriate therapy. Subclinical hypothyroidism should be considered a possible cause of painful neuropathy and replacement hormone treatment can reverse clinical, neurophysiological, and neuropathological abnormalities.

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© Springer-Verlag 2009