A 61 year-old man with exercise-induced muscle spasms

Transcription

1 A 61 year-old man with exercise-induced muscle spasms Jeffrey Ralph, MD RAIN 2017 Case Presentation 61 year-old man with hypertension 1 year ago: tingling in the hands, which then spread to neck, arms, and legs Diagnosed with B12 deficiency (149 ng/l) Sensory symptoms improved with B12 replacement ~ 6 mos. of generalized and worsening stiffness and weakness Recently noticed difficulty arising from chairs Case Presentation II Any movements lead to constant contraction; it takes his muscles 30 sec. to relax Limbs, trunk/abdomen/neck/facial muscles all affected. Speech and swallowing also affected. Lost 20 lbs. in past 4 mos. Case Presentation III: Exam Alert, oriented Speech-induced dysarthria- slurred (LMN) CN: limited abduction of the eyes; action-induced contractions of the facial muscles (video) Motor: normal tone and bulk; mild-to-moderate proximal limb weakness; grip myotonia but no percussion myotonia Areflexic. Mute plantar responses Sensory: Impaired pain sensation distal to mid-shin; absent vibration distal to ankles. Coordination: FNF and HKS normal and accurate 1

2 Video I Other information: Elevated anti-gad antibodies (>250 IU/mL) Normal MRI imaging of the brain and cervical spinal cord TRANSFER TO UCSF: STIFF PERSON SYNDROME What would you do next? A. 1. Full serum paraneoplastic panel B. 2. Lumbar puncture for CSF analysis C. 3. Toxicology consultation D. 4. Genetic testing All good answers, but something else done in this case 1. F u l l s e r u m p a r a n e o p l a... 54% 2. L u m b a r p u n c t u r e f o r... 27% 14% 5% 3. T o x i c o l o g y c o n s u l t a t i o n 4. G e n e t i c t e s t i n g Always do an EMG/NCS first! * Nerve Conduction Studies abnormal findings: Reduced motor nerve conduction velocities in two nerve segments (R median elbow-axillary and R ulnar AE-axillary segment) Prolonged F waves for 2/4 nerves Absent SNAPs in the lower extremities EMG very abnormal * Just kidding sort of 2

3 Video II: EMG Which is most likely? A. Positive Caspr2 Abs B. A CTG trinucleotide repeat expansion C. Frequently consumes local seafood D. Multiple sclerosis 59% 35% 6% 0% P o s i t i v e C a s p r 2 A b s A C T G t r i n u c l e o t i d e r e p e.. F r e q u e n t l y c o n s u m e s l o c a... M u l t i p l e s c l e r o s i s What was that EMG? Miss Him The discharges remind me of Isaacs Syndrome Electrographic Electrographic A burst of motor unit action potentials which originates in motor axons firing at high rates (150 to 300 Hz) for a few seconds Sounds like a Formula 1 Car Often start and stop abruptly. The amplitude of the waveforms typically wanes. Discharges may occur spontaneously or be initiated by needle electrode movement, voluntary effort, ischemia, or percussion of the nerve. These discharges should be distinguished from myotonic discharges and complex repetitive discharges. 19,000 RPM x 1 min/60 sec = 317 Hz 3

4 Neuromyotonic Discharge, II Sections from longer continuous EMG recordings illustrating decremental patterns and varying partial motor unit size occurring within high frequency bursts of neuromyotonia. On motor nerve conduction studies, trains of afterdischarges are often seen after supramaximal stimulation of nerves. Maddison P. Clinical Neurophysiology, Volume 117, Issue 10, 2006, Tibial motor nerve conduction study Additional Results VGKC, VGCC, Hu, Yo, Ri negative CSF WBC 2 protein 45 mg/dl; glucose 64 mg/dl CK Hemoglobin A1c (6/2) TSH , T3 3, T4 9 Anti-thyroglobulin antibodies Anti-thyroperoxidase antibodies 167 B12 - >2000 HIV - neg TPA - neg SPEP - Hypoalbuminemia, normal pattern Light chains - WNL IFE - Neg Anti-Intrinsic Factor: Positive Anti-GAD65 > 250 ESR 39 PET/CT neg for hypermetabolic lesions Fasciculations or Cramps or Cramp Fasciculation Syndrome Clinical neuromyotonia includes the following: Muscle twitches Muscle stiffness Cramps Hyperhidrosis Pseudo-myotonia Doublets, Triplets Myokymia PERIPHERAL NERVE HYPEREXCITABILITY SPECTRUM Peripheral Nerve Hyperexcitability Causes Immune Genetic Idiopathic/Miscellaneous Activity-induced neuromyotonia. Only seen in a minority of patients. 4

5 Generalized = Isaacs Syndrome Muscle twitches, Muscle stiffness, Cramps, Hyperhidrosis, Pseudo-myotonia Morvan s fibrillary chorea Morvan in 1890: La chorée fibrillaire Clinical features: Insomnia Delirium Dysautonomia Autoimmune Disease Associations with Myasthenia gravis Diabetes mellitus CIDP/GBS Celiac disease Pernicious Anemia Hyperthyroidism/hypothyroidism Vitiligo Infections Staphylococcal infections Toxins Herbicides, insecticides, toluene, timber rattle snake Paraneoplastic Small cell lung carcinoma Lymphoma Plasmacytoma Thymoma (with or without MG) Drugs Gold, oxaliplatin Genetic Hereditary neuropathy, KCNA1 mutations Clinical Course Channels and Nerve/Muscle Hyperexcitability Monophasic K+ Channelopathy Symptoms Time Symptoms Time Sodium Channelopathy Myotonia Chronic Progressive Relapsing-Remitting Chloride Channelopathy 5

6 VGKCs and Antibody in neuromyotonia discovered when dendrotoxin used in radiolabeled immunoprecipitation assay VGKCs found in about 40% of patients with neuromyotonia Limited yield partially related to dendrotoxin failure to block all members of the VGKC family Scatter plot of serum VGKC antibody titres in 39 patients with the neuromyotonia phenotype of autoimmune peripheral nerve hyperexcitability. Patients with thymoma are shown separately. Titres were considered positive if more than the mean plus 3 SDs. Maddison P.. Clinical Neurophysiology, Volume 117, Issue 10, 2006, The Expanding World of Autoantibodies Turns out that the VGKC antibodies are mostly targeting non-channel proteins complexed with Kv1 Caspr2 Abs Caspr2 = contactinassociated protein-like 2 VGKC ABS Lgi1 Abs Lgi1 = leucine-rich glioma inactivated 1 The Expanding World of Auto-antibodies CNS dysfunction/ Limbic Encephalitis LGI1 Caspr2 LGI1 Is the main autoantigen of limbic encephalitis previously attributed to VGKCs CASPR2 Is the autoantigen of encephalitis and PNH previously attributed to VGKCs It is possible (rare) to have antibodies to LGI1 and CASPR2 but not VGKCs Positive VGKCs but negative LGI1 and CASPR2 of debatable clinical significance. TAKE HOME: If neuromyotonia Check VGKC and CASPR2 (Many patients with neuromyotonia are negative for both VGKC and CASPR2) Which would be the wrong treatment for the patient? A. 3,4 Diaminopyridine B. Dronabinol C. Gabapentin D. Carbamazepine 3, 4 D i a m i n o p y r i d i n e 43% D r o n a b i n o l 13% G a b a p e n t i n 14% 30% C a r b a m a z e p i n e 6

7 Treatments Symptomatic Sodium Channel Blockers Carbamazepine, Phenytoin Miscellaneous Dronabinol (cannabinoid) Gabapentin Immune In paraneoplastic form, removal of neoplasm usually minimal effect PLEX more effective than IVIG Prednisone, azathioprine Patient Follow-Up Initial diagnosis was stiff person syndrome Referring Hospital Valium and IVIG prescribed no benefit UCSF Carbamazepine 400 mg twice daily marked improvement PLEX additional improvement Outpatient still symptomatic but not limited in his activities PLEX 1.5 plasma volume x 4, repeated monthly CBZ 400 mg three times daily Azathioprine 200 mg QD Acknowledgements Laura Rosow Kaitlin Greene Claire Clelland Maulik Shah Thanks for your attention! 7