Nivedita U. Jerath

Hereditary motor and sensory neuropathies: Understanding molecular pathogenesis could lead to future treatment strategies

Inherited peripheral neuropathies, like many other degenerative disorders, have been challenging to treat. At this point, there is little specific therapy for the inherited neuropathies other than genetic counseling as well as symptomatic treatment and rehabilitation. In the past, ascorbic acid, progesterone antagonists, and subcutaneous neurotrophin-3 (NT3) injections have demonstrated improvement in animal models of CMT 1A, the most common inherited neuropathy, but have failed to translate any effect in humans. Given the difficulty in treatment, it is important to understand the molecular pathogenesis of hereditary neuropathies in order to strategize potential future therapies. The hereditary neuropathies are in an era of molecular insight and over the past 20 years, more than 78 subtypes of Charcot Marie Tooth disease (CMT) have been identified and extensively studied to understand the biological pathways in greater detail. Next generation molecular sequencing has also improved the diagnosis as well as the understanding of CMT. A greater understanding of the molecular pathways will help pave the way to future therapeutics of CMT. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

Neuroleukemiosis: an unusual cause of peripheral neuropathy

Abstract Leukemia may initially present as a peripheral neuropathy, leading to a delay in diagnosis. Leukemic infiltration of peripheral nerves, or neuroleukemiosis (NL), is exceedingly rare, with no established diagnostic or therapeutic guidelines. Five cases are presented. All patients were men with a median age of 68 years (range 46–72). Three patients had acute myeloid leukemia (AML) and two had chronic lymphocytic leukemia (CLL). In two patients, leukemia presented with peripheral nerve involvement and both were found to have positive cerebrospinal fluid (CSF) cytology, making the diagnosis AML, despite negative bone marrow and peripheral smear. All patients had painful, progressive, motor and sensory deficits. Clinical patterns were mononeuropathy (n =1), multiple mononeuropathies (n =1) and plexopathy (n =3). Magnetic resonance imaging (MRI) detected mass lesions in 4/5 cases, with avid fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) useful in all of these for following clinical disease progression. Three cases of nerve biopsy were performed, two of which were diagnostic of leukemic infiltration. Radiation treatment rapidly relieved pain in patients with mass lesions, in combination with chemotherapy. Four patients had disease relapse, four systemic and one also in peripheral nerves. These cases are discussed in the context of the broader literature.

Options in Treating Trigeminal Neuralgia: Experience With 195 Patients.

OBJECTIVE For patients with medically unresponsive trigeminal neuralgia (TN), surgical options include microvascular decompression (MVD), radiofrequency rhizotomy (RF), and stereotactic radiosurgery (SRS). In an attempt to identify the risks and benefits and cost inherent with each of the three modalities, we performed a retrospective review of our experience with 195 cases of TN treated over the past 15 years. METHODS Since 2001, 195 patients with previously untreated TN were managed: with MVD in 79, RF in 36, and SRS in 80. All patients reported herein underwent preoperative MRI. Women outnumbered men 122/73 (p=0.045). Follow-up after surgery was 32±46months. RESULTS The patients qualifying for MVD were generally healthier and younger, with a mean age±SD of 57±14, compared to those undergoing RF (75±15) or SRS (73±13, p<0.0001). In case of relapse, medical treatment was always tried and failed prior to consideration of surgical intervention. A second surgical procedure was necessary in 2, 23, and 18 patients initially treated with MVD, RF, and SRS respectively (p<0.0001). In the patients treated with MVD, RF, and SRS, the average number of procedures per patient necessary to achieve pain control was 1.1, 2.0, and 1.3 respectively (p=0.001). There were 7 complications in the patients treated with MVD but no deaths. Numbness was present in 13, 18, and 29 patients treated with MVD, RF, and SRS respectively (p=0.008). CONCLUSION MVD for TN is the treatment least likely to fail or require additional treatment. Patients who underwent MVD were younger than those undergoing RF or SRS. The highest rate of recurrence of TN was encountered in patients undergoing RF (64%). Facial numbness was least likely to occur with MVD (16%) compared to RF and SRS (50% and 36% respectively).

Rare manifestation of a c.290 C>T, p.Gly97Glu VCP mutation

Introduction. The valosin-containing protein (VCP) regulates several distinct cellular processes. Consistent with this, VCP mutations manifest variable clinical phenotypes among and within families and are a diagnostic challenge. Methods. A 60-year-old man who played ice hockey into his 50s was evaluated by electrodiagnostics, muscle biopsy, and molecular genetics. Results. With long-standing pes cavus and toe walking, our patient developed progressive weakness, cramps, memory loss, and paresthesias at age 52. An axonal sensorimotor neuropathy was found upon repeated testing at age 58. Neuropathic histopathology was present in the quadriceps, and exome sequencing revealed the VCP mutation c.290 C>T, p.Gly97Glu. Conclusions. Our patient reflects the clinical heterogeneity of VCP mutations, as his neurological localization is a spectrum between a lower motor neuron disorder and a hereditary axonal peripheral neuropathy such as CMT2. Our case demonstrates a rare manifestation of the c.290 C>T, pGly97Glu VCP mutation.

A case of neuromyotonia and axonal motor neuropathy: A report of a HINT1 mutation in the United States

Introduction: HINT1 mutations cause an autosomal recessive distal hereditary motor axonal neuropathy with neuromyotonia. This is a case report of a HINT1 mutation in the United States. Methods: A 30‐year‐old man of Slovenian heritage and no significant family history presented with scoliosis as a child and later developed neuromyotonia and distal weakness. Electrodiagnostic testing revealed an axonal motor neuropathy and neuromyotonic discharges. Previous diagnostic work‐up, including testing for Cx32, MPZ, PMP‐22, NF‐L, EGR2, CLCN1, DM1, DM2, SMN exon 7/8, emerin, LMNA, MPK, SCNA4, acid maltase gene, paraneoplastic disorder, and a sural nerve biopsy, was negative. Results: Genetic testing for a HINT1 mutation was performed and revealed a homozygous mutation at p.Arg37Pro. Conclusion: This entity should be distinguished clinically and genetically from myotonic dystrophy and channelopathies with the clinical features of neuromyotonia and an axonal neuropathy. This case illustrates the importance of identifying the correct phenotype to avoid unnecessary and costly evaluations. Muscle Nerve 52: 1110–1113, 2015

Diagnostic Yield of FDG-PET/CT, MRI, and CSF Cytology in Non-Biopsiable Neurolymphomatosis as a Heralding Sign of Recurrent Non-Hodgkin's Lymphoma

Neurolymphomatosis (NL) is a rare condition associated with lymphomas in which various structures of the nervous system are infiltrated by malignant lymphocytes. Rarely, it may be the presenting feature of recurrence of lymphoma otherwise deemed to be in remission. It is crucial, as is the case with all types of nodal or visceral involvement of lymphoma, to identify the disease early and initiate treatment with chemotherapy and/or radiation therapy. Positron emission tomography-computed tomography (PET-CT) has been shown to be a sensitive modality for staging, restaging, biopsy guidance, therapy response assessment, and surveillance for recurrence of lymphoma. Magnetic resonance imaging (MRI) is another useful imaging modality, which, along with PET/CT, compliment cerebrospinal spinal fluid (CSF) cytology and electromyography (EMG) in the diagnosis of NL. Performing nerve biopsies to confirm neurolymphomatosis can be challenging and with associated morbidity. The case presented herein illustrates the practical usefulness of these tests in detecting NL as a heralding feature of lymphoma recurrence, especially in the absence of histopathologic correlation.

Epidural Spinal Cord Stimulation: A Novel Therapy in the Treatment of Restless Legs Syndrome

BACKGROUND We report a unique finding of a patient whose restless legs syndrome (RLS) symptoms abated after the placement of a spinal cord stimulator for chronic neuropathic pain. RLS is a common disorder, with many patients unable to find sufficient relief from their symptoms. CASE DESCRIPTION A patient diagnosed with neuropathic pain who also suffered from RLS symptoms despite medication therapy underwent implantation of a spinal cord stimulator after a successful trial. This patient was interviewed formally about his RLS symptoms immediately before his procedure and at 6 weeks, 6 months, and 2.5 years after the procedure. The patient also completed the International Restless Legs Syndrome Scale questionnaire to objectively quantify the severity of his symptoms. Finally, the patient kept a 5-day journal detailing when the stimulator was in use. The patient reported subjective symptomatic improvement in his RLS symptoms with improved sleep quality and quantity, in addition to improvement in his back pain. The patients score on the International Restless Legs Syndrome Scale improved after implantation from 33 to 0 on a 40-point scale. Moreover, when asked to keep a journal record of his stimulator use, the patient noted that he only used the stimulator before going to bed to help his RLS symptoms and no longer required any medication for his previous RLS symptoms. CONCLUSIONS Epidural stimulation may be an additional, alternative, or novel therapy in the treatment of RLS.

Charcot–marie–tooth disease type 1X in women: Electrodiagnostic findings

Introduction: Symptoms and signs in women with Charcot–Marie–Tooth disease type 1X (CMT1X) are often milder from those in men, but the available electrophysiologic evidence regarding CMT1X in women has been characterized in some patients as non‐uniform or asymmetric. Methods: We retrospectively reviewed electrodiagnostic findings from 45 women and 31 men with CMT1X. Results: Motor nerve conduction parameters in CMT1X women were less abnormal (P < 0.05), and a wider range of motor conduction velocities (CVs) were seen in women (P < 0.001) compared with men. In women, nerve conduction studies showed lack of conduction block without temporal dispersion. Motor CVs were more frequently in the normal range in women compared with men. There was no significant relationship to age of presentation and motor CV or compound muscle action potential in women. Conclusion: NCS parameters in CMT1X women did not demonstrate features suggestive of an acquired demyelinating neuropathy. Muscle Nerve, 2016 Muscle Nerve 54: –, 2016 Muscle Nerve 54: 728–732, 2016

Progressive Lower Extremity Weakness and Axonal Sensorimotor Polyneuropathy from a Mutation in KIF5A (c.611G>A;p.Arg204Gln)

Introduction. Hereditary Spastic Paraplegia (HSP) is a rare hereditary disorder that primarily involves progressive spasticity of the legs (hamstrings, quadriceps, and calves). Methods. A 27-year-old gentleman was a fast runner and able to play soccer until age 9 when he developed slowly progressive weakness. He was wheelchair-bound by age 25. He was evaluated by laboratory testing, imaging, electrodiagnostics, and molecular genetics. Results. Electrodiagnostic testing revealed an axonal sensorimotor polyneuropathy. Genetic testing for HSP in 2003 was negative; repeat testing in 2013 revealed a mutation in KIF5A (c.611G>A;p.Arg204Gln). Conclusions. A recent advance in neurogenetics has allowed for more genes and mutations to be identified; over 76 different genetic loci for HSP and 59 gene products are currently known. Even though our patient had a sensorimotor polyneuropathy on electrodiagnostic testing and a 2003 HSP genetic panel that was negative, a repeat HSP genetic panel was performed in 2013 due to the advancement in neurogenetics. This revealed a mutation in KIF5A.

Factors influencing aversion to specific electrodiagnostic studies.

To compare the degree of discomfort caused by nerve conduction studies (NCS) versus needle electromyography (EMG), and to determine what factors predict aversion to one test or the other.