Mild Distal Weakness Research Articles

Expanding the Spectrum of Chronic Immune Sensory Polyradiculopathy

ObjectiveSensory loss with normal nerve conduction studies (NCS) from focal sensory root inflammatory demyelination is characteristic of chronic immune sensory polyradiculopathy (CISP). However, nonpure cases involving motor and distal sensory nerves exist (CISP-plus). We hypothesize that CISP-plus and CISP are fundamentally part of the same syndrome through comparison of clinical, neurophysiologic, and pathologic features.MethodsCISP-plus (primary dorsal root with lesser motor and sensory nerve involvement) and CISP cases were retrospectively analyzed (1986–2019).ResultsWe identified 44 CISP-plus and 28 CISP cases (n = 72) with 86% (38/44) of patients with CISP-plus and 79% (22/28) of patients with CISP experiencing imbalance. On examination, large fiber sensory loss was present in 98% (43/44) of patients with CISP-plus and 96% (27/28) of patients with CISP. Gait ataxia was evident in 93% (41/44) of patients with CISP-plus and 79% (22/28) of patients with CISP. Mild distal weakness was common in CISP-plus (75%, 33/44). NCS showed mild abnormalities in all patients with CISP-plus and were normal (by definition) in all patients with CISP. Elevated CSF protein, slowing of somatosensory evoked potentials, and MRI root enhancement occurred in most CISP-plus and CISP cases. Eleven CISP-plus nerve biopsies showed loss of large myelinated fibers and onion-bulb formations, most prominent in rootlet biopsies. Immunotherapy resulted in marked improvement of gait ataxia in 84% (27/32) of patients with CISP-plus and 93% (13/14) of patients with CISP with return to normal neurologic examination in half (25/46).ConclusionThe recognition of CISP-plus expands the spectrum of CIDP by combining CISP-plus (predominant sensory polyradiculopathy with mild motor and sensory nerve involvement) with pure CISP (focal sensory polyradiculopathy) together as proximal sensory CIDP.

Episodic psychosis, ataxia, motor neuropathy with pyramidal signs (PAMP syndrome)caused by a novel mutation in ADPRHL2 (AHR3).

The protein "ADP-Ribosylarginine Hydrolase-Like Protein 2" is encoded by ADPRHL2 and reverses ADP-ribosylation. Recently, mutations in ADPRHL2 were found to be associated with a very rare childhood onset severe neurodegeneration syndrome with episodic, stress-induced seizures, ataxia, and axonal neuropathy. In this study, we evaluate a novel mutation in ADPRHL2 leading to an unknown adult onset syndrome "episodic psychosis, ataxia, motor neuropathy with pyramidal signs(PAMP syndrome)." Four patients with episodic psychosis, ataxia, and motor neuropathy with pyramidal signs were included in this study. An index patient presented ataxia, postural tremor in the hands, and hallucinations at age 20 years, which had started after a viral infection. She improved within 3 months without any treatment. Her neurological exam revealed mild distal weakness, brisk DTRs, bilateral Babinski sign, impaired vibration sensation, position, and ataxia. Pes cavus and hammer toes were also noted. EMG revealed neurogenic changes in distal muscles and normal sensory nerve conduction studies. Cranial MRI was normal. She had three more severe episodes in recent years, and her neurologic findings got progressively worse. Two of her older sisters had much milder phenotypes. The phenotype of the fourth patient from an unrelated family was identical with the index patient. All affected patients had homozygous novel NM_017825.3:c.838G>A (p.Ala280Thr) mutations in a highly conserved region of ADPRHL2. Western blot analyses demonstrated that ADPRHL2 was not expressed in these patients. Here, we describe a novel mutation in ADPRHL2, which further expands the phenotypic and genetic spectrum of the patients harboring these mutations.

Late adult-onset Hereditary Sensory and Motor Neuropathy due to TECPR2 mutations

Objective: The description of a new genetic association with late-onset axonal Charcot-Marie-Tooth disease (CMT). Method. A 57-year-old Brazilian woman presented with a slowly progressive history of paresthesia, muscle wasting and weakness in her lower limbs since age 50 years. Examination disclosed peroneal amyotrophy, bilateral pes cavus, mild distal weakness, reduced vibration, pain and temperature sensation in the the lower limbs and brisk tendon reflexes. Results. Neurophysiological studies showed chronic sensorimotor axonal polyneuropathy. Whole-genome sequencing showed compound heterozygous pathogenic variants in the TECPR2 gene (14q32.31). Conclusion. This novel genetic presentation of late-onset axonal CMT with brisk tendon reflexes associated with TECPR2.

Severe myotonia in juvenile myotonic dystrophy type 2 and sodium channel gene mutation

Severe myotonia in juvenile myotonic dystrophy type 2 and sodium channel gene mutation

Distal Acquired Demyelinating Symmetric Neuropathy After Vaccination

Neuropathy after vaccination is a rare event. Chronic immune-mediated polyneuropathy developing in the postvaccination period is distinctly unusual and not well described. Almost all such patients have been reported as having typical chronic inflammatory demyelinating polyneuropathy. Distal acquired demyelinating symmetric neuropathy, unlike classic chronic inflammatory demyelinating polyneuropathy, is characterized by distally predominant sensory symptoms with no or mild distal weakness. We describe the clinical, laboratory, and neurophysiological findings of 2 patients who developed distal acquired demyelinating symmetric neuropathy after vaccination. Immunomodulatory therapy led to clinical improvement in both cases. The literature is reviewed with attention to the clinical features of chronic immune-mediated neuropathies that follow vaccination.

Molecular diagnosis of hereditary inclusion body myopathy by linkage analysis and identification of a novel splice site mutation in GNE

BackgroundMany myopathies share clinical features in common, and diagnosis often requires genetic testing. We ascertained a family in which five siblings presented with distal muscle weakness of unknown etiology.MethodsWe performed high-density genomewide linkage analysis and mutation screening of candidate genes to identify the genetic defect in the family. Preserved clinical biopsy material was reviewed to confirm the diagnosis, and reverse transcriptase PCR was used to determine the molecular effect of a splice site mutation.ResultsThe linkage scan excluded the majority of known myopathy genes, but one linkage peak included the gene GNE, in which mutations cause autosomal recessive hereditary inclusion body myopathy type 2 (HIBM2). Muscle biopsy tissue from a patient showed myopathic features, including small basophilic fibers with vacuoles. Sequence analysis of GNE revealed affected individuals were compound heterozygous for a novel mutation in the 5' splice donor site of intron 10 (c.1816+5G>A) and a previously reported missense mutation (c.2086G>A, p.V696M), confirming the diagnosis as HIBM2. The splice site mutation correlated with exclusion of exon 10 from the transcript, which is predicted to produce an in-frame deletion (p.G545_D605del) of 61 amino acids in the kinase domain of the GNE protein. The father of the proband was heterozygous for the splice site mutation and exhibited mild distal weakness late in life.ConclusionsOur study expands on the extensive allelic heterogeneity of HIBM2 and demonstrates the value of linkage analysis in resolving ambiguous clinical findings to achieve a molecular diagnosis.

Pupil-Involving Third Nerve Palsy as a Manifestation of Anti-Myelin–Associated Glycoprotein Neuropathy

A 56-year-old man developed a pupil-involving left third nerve palsy. Imaging studies of the brain and intracranial vessels were normal. Neurological examination demonstrated a sensory polyneuropathy and mild distal weakness. Nerve conduction studies showed prolonged distal motor latencies. An enzyme-linked immunosorbent assay test detected high titers of anti-myelin-associated glycoprotein (MAG) antibodies. The patient improved with prednisone and rituximab treatment. Anti-MAG neuropathy should be considered when evaluating a patient with an undiagnosed cranial neuropathy, especially in the setting of a sensory neuropathy.

Diabetic lumbosacral radiculoplexus neuropathy: a postmortem studied patient and review of the literature

Peripheral neuropathy is an important complication of diabetes mellitus. A particular type of proximal diabetic neuropathy, lumbosacral radiculoplexus neuropathy (DLSRPN), presents with pelvi-femoral pain followed by weakness, beginning focally in the upper leg or thigh with spread to the contralateral limb, and variable weight loss [1]. Ischemic nerve injury due to microscopic vasculitis has been a widely postulated unifying hypothesis of DLSRPN and derived from one well studied postmortem case reported 4 decades ago, the finding of microscopic vasculitis in proximal or distal cutaneous nerve biopsy tissue and the favorable response to immunotherapy. A 59 year old man with diabetes mellitus for 15 years treated with oral hypoglycemic medication noted left thigh pain, paresthesia, and impotence commencing in January 1995. This was followed by sensory changes and weakness first in the left leg then in the other in a stepwise fashion leading first to the necessity of a cane, then walker accompanied by a 15 lb weight loss, until he was essentially bed-bound and admitted to the hospital in June 1995. Admission neurological examination showed wasting and near-flail weakness in the legs from the thighs to the toes with rare limb fasciculation, mild distal weakness of the hands in the distribution of the distal median and ulnar nerves, mild stocking sensory loss to light touch, vibratory and cold temperature stimulation to just above the knee, areflexia, and otherwise intact cranial nerves and cognition. Admission laboratory studies showed erythrocyte sedimentation rate 60 mm/hour (normal \20), fasting blood glucose 250 mg/dL (normal \105), and hemoglobin A1C level 7.1% (normal \6). Causes of neuropathy other than diabetes mellitus were excluded by appropriate investigations. Nerve conduction studies and electromyography (EMG) of the right arm and leg showed axonal neuropathy with acute and chronic denervation in proximal and distal limb muscles including lumbosacral paraspinal muscles. Cerebrospinal fluid showed total protein 122 mg/dL (normal\45) and glucose 88 mg/dL with 12 white blood cells/ mm (normal \5). Right sural nerve biopsy showed features of microvasculitis (MV). Inflammatory cells surrounded a small epineurial artery with extension into the vascular wall, with reactive luminal connective tissue suggesting recanalization of a thrombus. An adjacent nerve fascicle showed marked loss of myelinated nerve fibers. The patient was treated for painful diabetic lumbosacral plexopathy and peripheral nerve vasculitis according to prevailing standards with 2 g/kg intravenous immunoglobulin for 5 days, followed by 750 mg of intravenous cyclophosphamide and 1,000 mg of methylprednisolone intravenously for 3 additional days. This was followed by acute tubular necrosis, increasing lethargy, unresponsiveness, and aspiration pneumonia requiring mechanical ventilation. He expired 4 weeks after admission. General autopsy showed no evidence of systemic or peripheral nerve vasculitis. The brain showed diffuse loss of neurons in all sampled cortical areas, including the cerebellum, consistent with anoxia secondary to cardiac arrest. Sections of extradural lumbar plexus, sciatic, and femoral nerve tissue showed perivascular epineurial inflammation with infiltration of adjacent endoneurium (Fig. 1a, b). Perivascular inflammation, not MV, was noted in postmortem nerve tissue in our patient. Although the D. S. Younger (&) Department of Neurology, New York University School of Medicine, 333 East 34th Street, Suite 1J, New York, NY 10016, USA e-mail: david.younger@nyumc.org

Peripheral neuropathy in patients with primary antiphospholipid (Hughes’) syndrome

The involvement of the peripheral nervous system in diverse autoimmune diseases is well established. However, no appropriately designed studies have been performed in primary antiphospholipid syndrome (PAPS)-related peripheral neuropathy. We aimed to investigate the occurrence of peripheral neuropathy in patients diagnosed with PAPS. Twenty-six consecutive patients with PAPS (Sapporo criteria) and 20 age- and gender-matched healthy controls were enrolled at two referral centers. Exclusion criteria were secondary causes of peripheral neuropathy. A complete clinical neurologic exam followed by nerve conduction studies (NCS) was performed. Paresthesias were reported in eight patients (31%). Objective mild distal weakness and abnormal symmetric deep tendon reflexes were observed in three patients (11.5%). With regard to the electrophysiologic evidence of peripheral neuropathy, nine patients (35.0%) had alterations: four (15.5%) had pure sensory or sensorimotor distal axonal neuropathy (in two of them a carpal tunnel syndrome was also present) and one (4%) had sensorimotor demyelinating and axonal neuropathy involving upper and lower extremities, while four patients (15.5%) showed isolated carpal tunnel syndrome. Clinical and serologic results were similar in all the patients with PAPS, regardless of the presence of electrophysiologic alterations. In conclusion, peripheral neuropathy is a common asymptomatic abnormality in patients with PAPS. The routine performance of NCS may be considered when evaluating such patients.

NEUROSURGICAL TREATMENT OF TREMOR IN ANTI-MYELIN-ASSOCIATED GLYCOPROTEIN NEUROPATHY

Anti-myelin-associated glycoprotein (anti-MAG) neuropathy is an antibody-mediated demyelinating neuropathy, with monoclonal immunoglobulin M (IgM) antibodies. It is characterized by a progressive, symmetric, mainly sensory neuropathy and mild distal weakness.1,2 Gait disorder with ataxia is a prominent feature.2 Limb tremor is common, while head, chin, and voice tremor do not occur.2 We report a case of a patient with anti-MAG neuropathy and tremor who had a marked improvement in tremor and quality of life with unilateral thalamic deep brain stimulation (DBS). There have been few other case reports in the literature regarding neuropathic tremor and DBS.3 ### Case report. A right-handed 82-year-old woman with no family history of tremor presented with hand and feet paresthesia, followed by the development of hand tremor 12 months later. Diagnosis of anti-MAG neuropathy was made serologically. Neurophysiologic studies confirmed the presence of a demyelinating, sensorimotor neuropathy with prolongation of the distal motor latencies. The tremor was disabling and prevented feeding and dressing herself as well as performing personal hygiene activities. Corticosteroids, plasma exchange, and IV cyclophosphamide were tried for 12 months without benefit. Primidone and gabapentin also gave little effect. Propranolol was contraindicated due to asthma. Rituximab …

Autologous peripheral blood stem cell transplantation in a patient with POEMS syndrome

Dear Editor, A 32-year-old woman was admitted because of progressive numbness in the lower limbs for 15 months, accompanied with pains in the breastbone, spine, and pelvis for 6 months before hospitalization. There was no prior history of exposure to neurologic toxins and no family history of neuropathy. Physical examination revealed splenomegaly, and no hyperpigmentation or other skin changes were observed. Neurological examination demonstrated moderate sensory disturbance of both lower limbs, with disappearance of deep tendon reflexes. Laboratory analysis showed that full blood count and urine routine test are normal. Other normal or negative results include hepatic and renal functions test, folate and VitB12 levels, and auto-antibody screen. Ophthalmoscopy revealed bilateral papilledema. Endocrinologic investigations showed low levels of FT3, FT4, testosterone, and estrogen. Electromyographic analysis demonstrated peripheral motor and sensory nerves demyelinating lesions in upper and lower limbs. Multiple osteosclerotic lesions in ribs, breastbone, spine, and pelvis were disclosed by CT scan (Fig. 1), together with a few lytic lesions in pelvis. Monoclonal IgG (κ) (20.3 g/l)(normal, 7.0–17.0 g/l) was detected in the serum by electrophoresis. There was no Bence-Jones proteinuria. Bone marrow aspiration revealed 2% of mature plasma cell with normal cytogenetics. Normal levels of protein, glucose and cells were detected in the cerebrospinal fluid (CSF). The patient met the criteria for the diagnosis of POEMS syndrome described by Dispenzieri [1]. She was initially treated with two cycles of chemotherapy with MP regimen (melphalan 6 mg/day days 1–7, Dexamethasone 40 mg/day, days 1–4, days 9–12, days 17–20). A minor improvement of numbness in the lower limbs was observed after chemotherapy, with disappearance of splenomegaly and papilledema, but the patient started to present with mild distal weakness of both lower limbs and toes. Bone pains in the breastbone, spine, and pelvis remained, but were stable. As she developed motor deficiency despite systemic chemotherapy, 5 months after diagnosis, she received autologous peripheral blood stem cell transplantation (autoPBSCT). Peripheral blood stem cell collection was performed after mobilization by chemotherapy (intravenous cyclophosphamide 60 mg/kg/day × 2 days), plus subcutaneous granulocyte colony-stimulating factor (rhG-CSF, 5 mg/kg/day) 6 days after chemotherapy and lasted for 3 days. The number of collected mononuclear cells (MNC) was 6.70×10/kg, and the CD34 cells were 7.51×10/kg. High-dose chemotherapy and autoPBSCT were performed 44 days after PBSC collection. She was conditioned using 200 mg/m melphalan, and the PBSC were infused 3 days later. Standard supportive care with prophylactic antibiotics was used before transplantation. Growth factor support was provided 3 days after stem cell transfusion. The transplantation course was uneventful except for a transient neutropenic fever and mucositis, which were settled with broad-spectrum antibacterial therapy. The patient was engrafted and the time to neutrophil count above 0.5×10/ l and platelets above 20×10/l was +10 and +11 days, respectively. Numbness in lower limbs improved gradually, and the area of sensory disturbance of numbness was limited in the bottoms of feet 6 months after transplantation, although Ann Hematol (2008) 87:247–248 DOI 10.1007/s00277-007-0379-2

Chronic inflammatory demyelinating polyradiculoneuropathy with tumefactive central demyelination

A 46-year-old man with a 1-year history of distal paresthesias and mild distal weakness subacutely developed paralysis of the left hand. Electrodiagnostic evaluation revealed a demyelinating peripheral neuropathy that met criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Magnetic resonance imaging of the brain revealed a mass that enhanced with contrast, but revealed focal myelin loss with intense macrophage activity and axonal preservation on biopsy. The mass and hand weakness improved following steroid therapy. The combination of CIDP and central demyelination with mass effect broadens the spectrum of demyelinating disease in association with CIDP.

Familial polyneuropathy with anti-myelin-associated glycoprotein antibodies

We describe the occurrence of the anti-myelin-associated glycoprotein (anti-MAG) syndrome, a well-recognized variant of chronic inflammatory demyelinating polyneuropathy (CIDP) with distinct clinical and electrophysiologic characteristics, in two brothers. A 70-year-old man presented with symmetric numbness distal to his knees, followed by progressive imbalance and gait unsteadiness that developed over 2 years. His similarly affected brother is described below (Case 2); there was no other relevant family history. On examination he had mild distal weakness in both lower limbs and symmetric vibration and proprioceptive loss distally in all four limbs. Muscle stretch reflexes were absent. Gait was severely ataxic and Romberg's sign was present. Nerve conduction studies revealed a severe demyelinating polyneuropathy with disproportionate distal slowing, prolongation of F waves without evidence of conduction block, and met criteria for CIDP.1 Immunoglobulin M (IgM) kappa monoclonal gammopathy was identified; IgM was 235 mg/dL (normal, 50 to 200 mg/dL) of which 50% to 90% was monoclonal and anti-MAG reactivity was positive at a titer of …

NON‐UNIFORM CONDUCTION SLOWING IN X‐LINKED DOMINANT CHARCOT‐MARIE‐TOOTH DISEASE (CMTX)

In hereditary demyelinating neuropathies conduction slowing has been reported to be uniform between and within nerves. This practical criterion has been used in the differential diagnosis with acquired demyelinating disorders. We report a 55‐year‐old man complaining of weakness and paresthesias of right hand and weakness of right leg. Examination showed bilateral pes cavus, difficulty to walk on heels, mild distal weakness in upper limbs, more on the right, and reduced reflexes in lower limbs. CSF was normal. Electrophysiological study showed a demyelinating sensory‐motor polyneuropathy with non‐uniform slowing of motor conduction, abnormal amplitude reduction with temporal dispersion of proximal motor responses in median and ulnar nerves. Sural biopsy was consistent with a demyelinating neuropathy. Chronic inflammatory demyelinating polyneuropathy (CIDP) was diagnosed and the patient treated with prednisone with improvement of paresthesias. Four years later the patient's brother, 57 years old, was referred for cramps, fasciculations and paresthesias in extremities. Examination showed mild distal weakness and atrophy, pes cavus, and reduced or absent reflexes. CSF examination showed slightly increased proteins and conduction slowing was uniform. Molecular analysis revealed in both patients an Arg(15)Gln Cx32 mutation.Non‐uniform conduction slowing has been recently re‐ ported in a CMTX family with Arg(15)Trp mutation (same codon of our patients) and in a woman with a non sense mutation at codon 102. The possibility of a CIDP‐like electrophysiological pattern in some CMTX patients should be kept in mind to avoid misdiagnoses.

Mapping of the gene for X-linked dominant Charcot-Marie-Tooth neuropathy.

We performed a clinical study and linkage analysis on 278 subjects (66 affected) belonging to eight families with X-linked dominant Charcot-Marie-Tooth (CMT) neuropathy. This form affects 11.8% of CMT patients in Iowa. Motor nerve conduction velocities (MNCVs) were significantly slowed consistent with type 1 CMT. Fifty-six obligate carriers manifested mild distal weakness, localized areflexia, pes cavus, and slowing on MNCVs. Seven X-linked restriction fragment length polymorphisms mapping in the Xp11-q21 region were tested for linkage against CMT. Two-point linkage results showed the highest lod scores with PGK1, DXS159, and DXYS1. Multipoint linkage analysis excluded the CMT gene from being telomeric to either DXS14 or DXYS1, with over 1,000:1 odds. The highest location scores were at PGK1 and 1 cM proximal to DXS159.