Lhermitte Sign

Etiology

Lhermitte's sign (LS) is not a disease but more of a sign or symptom. The sign is suggestive of a lesion or compression of the lower brainstem or the upper cervical spinal cord. It is a paroxysmal sensation or neuropathic pain that can develop as a result of direct or indirect demyelinating lesions in the brain and/or spinal cord and is triggered by the flexion or movement of the neck. More specifically, the neck motion activates ascending spinothalamic tracts at the cervical level that has been sensitized by the underlying process that caused the cervical spine lesion.[5] This view is supported by an MRI study of plaque formations in the cervical spine, which was found in 95% of those reporting a history of LS compared with 52% of those who did not report the sign.[6]

Other etiologies that have been shown to cause this sign, in addition to multiple sclerosis, include conditions like Bechet's disease, transverse myelitis, systemic lupus erythematosus (SLE), herpes zoster, Arnold-Chiari malformation, tumor progression causing spinal cord compression, radiculopathy, cervical spondylitis, transverse myelitis, syringomyelia, vitamin b12 deficiency, nitric oxide toxicity, subacute combined degeneration of the cord, radiation myelopathy, and chemoradiation. It is preferentially present in patients with cervical demyelinating lesions and abnormal nerve conduction studies. It is not a sensitive or specific sign for any of the disorders mentioned. Neck flexion irritates demyelinated tracts in the posterior column, causing the electric sensation experienced by patients.[7][8][9]

Epidemiology

Epidemiological studies of the incidence and prevalence of Lhermitte's sign are scant and give varying data, and there are no available statistics regarding the incidence or prevalence of Lhermitte's sign in today's global population.[10][11] However, the overall prevalence of Lhermitte's sign in patients with MS ranges from 9 to 41%.[12][6] One prospective study from 2015 of almost 700 patients with MS showed an incidence of about 16%, while another older study from 1982 reported that Lhermitte's sign was experienced by 33.3% of patients, with around 16% reporting having it occurring during their first episode of MS.[13][14][5] 

Despite the low sensitivity in those with MS, it has been said to have a very high specificity of 97% for compressive myelopathy as the underlying etiology.[15] One study also compared the prevalence in patients with MS and neuromyelitis optica (NMO). They found that the prevalence of Lhermitte's sign among MS patients (4.3%) was significantly lower than in NMO patients (20.5%) (P < 0.0001).[16] Lhermitte's sign was also found to be more common in patients with a family history of Lhermitte's sign in patients with NMO than in MS, at 12.5% vs. 5.9%, respectively. Although this symptom is typically self-limiting with spontaneous resolution after some weeks, occasionally, patients complain of increasing frequency and pain intensity.[17] The incidence and prevalence of Lhermitte's sign in rarer etiologies like vitamin B12 deficiency, Behcet disease, and SSRI discontinuation syndrome, among others, have not been well studied. 

Pathophysiology

The pathophysiology of Lhermitte's sign that is associated with the radiographical demyelinating lesions and electrodiagnostic abnormalities on nerve conduction is thought to be related to the demyelination of the dorsal columns of the cervical spine. Other reasons include compressive myelopathy with reported lesions in the dorsal columns of the caudal medulla. It is also thought to transiently activate neuropathic pain pathways, with a more recent theory being that it implicates glutamatergic signaling and microglial cell activation in the CNS.

Lhermitte's sign is thought to result from ectopic firing and hyperexcitability of demyelinated sensory neurons (in cervical regions of the spinal cord), also affecting ascending spinothalamic nociceptive signal transduction and impaired function of inhibitory GABAergic interneurons. Other proposed molecular mechanisms include downstream activated microglia that enhance pro-inflammatory cytokine signaling, activation of proteins like bradykinin with B1 and B2 receptors, upregulation of Wnt signaling, CREB phosphorylation, and other transcription factors in the CNS that augment hyperexcitability and pain.[9][18]

History and Physical

Neck movements, fatigue, stress, heat, and even yawning have been shown to trigger Lhermitte's sign.[5] Patients often describe Lhermitte's sign as an electric shock of pain that runs from the head down to the back and through the arms and legs. It happens when they bend their head down (flex their neck) and touch their chin to their chest.[7] In addition to neck flexion, it has also been described with neck extension (reverse Lhermitte's sign).[19]

Evaluation

There is no routine laboratory, radiological, or ancillary test to assess or manage Lhermitte's sign. Some prospective studies link the sign with radiographic and electrodiagnostic findings. One study showed a correlation between the clinical signs, the presence of a demyelinating lesion on cervical MRI, and the conduction delay of median and tibial somatosensory evoked potentials (SSEP). The results were clinically and statistically significant. However, the consensus is that the history and physical exam findings are sufficient.[13][7]

Treatment / Management

There is an absence of level I evidence-based treatment for those suffering from Lhermitte's sign, given the vast number of etiologies causing the condition. LS rarely elicits severe pain and discomfort as it is usually a benign finding and self-resolves. Treatment of the underlying condition, like in MS, and surgically addressing any of the compressive anatomical causes are recommended. Few reports and anecdotal evidence show that carbamazepine, oxcarbazepine, and gabapentin may benefit some patients.[20][21] Inhibition of pro-inflammatory cytokine signaling, augmentation of inhibitory cytokine signaling, and blockade of chemokine receptor-mediated inflammatory cell recruitment to the CNS has the potential for future therapies for more severe manifestations of MS-associated neuropathic pain.[9](B3)

Interestingly, a case series demonstrated that the use of extracranial picotesla range pulsed electromagnetic fields (EMFs) effectively treated patients with Lhermitte's sign. One theory is that the reduction of axonal excitability occurs through the modulation of ionic membrane permeability. The second theory involves modulating pain control systems through neurotransmitter activity and pineal melatonin functions, as discussed earlier.[22][23](B3)

Differential Diagnosis

The differential diagnosis of Lhermitte sign, besides MS, has been reported in the literature and includes tumor progression causing spinal cord compression, radiculopathy, cervical spondylitis, transverse myelitis, subacute combined degeneration of the cord, radiation myelopathy, parasitic invasion of the cord, Arnold-Chiari malformation, high dose chemoradiation (cisplatin), trauma, arachnoiditis, Herpes zoster toxicity, syringomyelia,  Behcet disease, vitamin B12 deficiency, nitric oxide toxicity, systemic lupus erythematous, and post-dural puncture headache.[24][25][26][19]

Radiation Oncology

Lhermitte's sign has been noted as a potential side effect of radiation oncology therapies, specifically as an early delayed radiation injury. These often occur within four months of radiation therapy.[27][25]

Medical Oncology

Cisplatin or docetaxel neurotoxicity has been tied to Lhermitte's sign.[25]

Prognosis

Lhermitte's sign or syndrome is not a disease process, and it is usually intermittent upon neck flexion. The prognosis of the disease process underlying the Lhermitte's sign is variable.

Complications

There are no known complications related to Lhermitte's sign. However, it is occasionally reported as a facet of a discontinuation syndrome related to certain medications. Psychotropic medications such as SSRIs and SNRIs, specifically paroxetine and venlafaxine, have been shown to have a reported association. Fluoxetine, given the extended length of its half-life, has less likelihood of causing Lhermitte's sign upon sudden discontinuation.[24] On the other hand, paroxetine has a shorter half-life and is more likely to cause discontinuation syndrome. In dentistry, there have been studies that found Lhermitte's sign associated with nitrous oxide abuse (caused by depletion of vitamin B12).[26][19]