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Case Presentation A 61 year-old man with
61 year-old man with hypertension exercise-induced muscle
1 year ago: tingling in the hands, which then spasms 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
Jeffrey Ralph, MD Recently noticed difficulty arising from chairs RAIN 2017

Case Presentation II Case Presentation III: Exam
Alert, oriented
Any movements lead to constant
Speech-induced dysarthria- slurred (LMN) contraction; it takes his muscles 30 sec. to
relax CN: limited abduction of the eyes; action-induced contractions of the facial muscles (video)
Limbs, trunk/abdomen/neck/facial muscles all
Motor: normal tone and bulk; mild-to-moderate affected.
proximal limb weakness; “grip myotonia” but no Speech and swallowing also affected. percussion myotonia
Lost 20 lbs. in past 4 mos.
Areflexic. Mute plantar responses
Sensory: Impaired pain sensation distal to mid-shin; absent vibration distal to ankles.
Coordination: FNF and HKS – normal and accurate

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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? Always do an EMG/NCS first!

A. 1. Full serum paraneoplastic panel
Nerve Conduction Studies – abnormal findings: B.
Reduced motor nerve conduction velocities in two 2. Lumbar puncture for CSF analysis 54% nerve segments (R median elbow-axillary and R C. 3. Toxicology consultation ulnar AE-axillary segment) D. 4. Genetic testing 27%
Prolonged F waves for 2/4 nerves 14%
5% Absent SNAPs in the lower extremities
EMG very abnormal… . g i n l a . . i o n p . . . t All good answers, but something elseo o r t e s t e e f i c c o n s u l t a p a r a n n c t u r e n e t u G 4 . a r p e r u m b done in this case… l s u l F . L u m 1 . 2 3. Toxicology * Just kidding…sort of

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Video II: EMG Which is most likely?

A. Positive Caspr2 Abs B. A CTG trinucleotide repeat expansion59% C. Frequently consumes local seafood D. Multiple sclerosis 35%

6% 0%

. c a . . . l o e s otide repe. u m l e i tive Caspr2 A bs c n s o s M ultiple sclerosis P r i n u t l y c o n T G t C A F r e q u e

The discharges Electrographic Neuromyotonia What was that EMG? remind me of Isaacs Syndrome
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 Electrographic myotonic discharges and complex repetitive discharges. Miss Him Neuromyotonia 19,000 RPM x 1 min/60 sec = 317 Hz

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On motor nerve conduction studies, trains of after- Neuromyotonic Discharge, II discharges are often seen after supramaximal

Sections from longer continuous stimulation of nerves. EMG recordings illustrating decremental patterns and varying partial motor unit size occurring within high frequency bursts of neuromyotonia .

Maddison P. Neuromyotonia Clinical Neurophysiology, Volume 117, Issue 10, 2006, 2118–2127

Tibial motor nerve conduction study

Additional Results Neuromyotonia Fasciculations or

Cramps or Doublets, VGKC, VGCC, Hu, Yo, Ri – TPA - neg Myokymia Neuromyotonia Cramp Fasciculation Triplets negative

SPEP - Hypoalbuminemia, Syndrome CSF WBC 2 protein 45 mg/dL; PERIPHERAL NERVE HYPEREXCITABILITY SPECTRUM glucose 64 mg/dL normal pattern
Peripheral Nerve Hyperexcitability
CK - 181 Light chains - WNL • Causes

Hemoglobin A1c - 5.2 (6/2) IFE - Neg • Immune •
TSH - 8.22, T3 3, T4 9
Genetic Anti-Intrinsic Factor: •
Idiopathic/Miscellaneous Anti-thyroglobulin antibodies - Positive 2.21

Clinical neuromyotonia includes the following:
Anti-GAD65 > 250 Anti-thyroperoxidase antibodies

Muscle twitches 167 ESR 39

Muscle stiffness B12 - >2000

Cramps Activity-induced neuromyotonia. HIV - neg

PET/CT – neg for Hyperhidrosis Only seen in a minority of hypermetabolic lesions
Pseudo-myotonia patients.

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Disease Associations with Neuromyotonia Neuromyotonia

Autoimmune
Paraneoplastic Generalized Neuromyotonia = Isaacs Syndrome


Myasthenia gravis Small cell lung carcinoma Muscle twitches, Muscle stiffness, Cramps,
Diabetes mellitus
Lymphoma Hyperhidrosis, Pseudo-myotonia
CIDP/GBS
Plasmacytoma


Morvan’s fibrillary chorea Celiac disease Thymoma (with or without
Pernicious Anemia MG)
Morvan in 1890: “La chorée fibrillaire”
Hyperthyroidism/hypothyroidism
Drugs

Clinical features: Vitiligo
Gold, oxaliplatin


Neuromyotonia Infections Genetic
Staphylococcal infections

Insomnia Hereditary neuropathy,
KCNA1 mutations
Toxins Delirium

Herbicides, insecticides, toluene, Dysautonomia timber rattle snake

Channels and Nerve/Muscle Hyperexcitability Clinical Course

Monophasic K+ “Channelopathy” Neuromyotonia

Symptoms Symptoms Symptoms Symptoms Sodium Channelopathy

Time Time Myotonia

Chronic Progressive Relapsing-Remitting Chloride Channelopathy

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VGKCs and Neuromyotonia The Expanding World of Auto- antibodies
Antibody in neuromyotonia discovered when dendrotoxin used in VGKC ABS radiolabeled Caspr2 immunoprecipitation assay Abs
VGKCs found in about Lgi1 Abs 40% of patients with

neuromyotonia 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. Limited yield partially related Titres were considered positive if more than the mean plus 3 SDs. to dendrotoxin failure to Maddison P. Neuromyotonia. Clinical Neurophysiology, Volume Turns out that the VGKC antibodies 117, Issue 10, 2006, 2118–2127 block all members of the are mostly targeting non-channel Caspr2 = contactin- Lgi1 = leucine-rich proteins complexed with Kv1 associated protein-like 2 glioma inactivated 1 VGKC family

The Expanding World of Auto-antibodies Which would be the wrong treatment for the patient? Caspr2 CNS dysfunction/ 43% Neuromyotonia Limbic Encephalitis A. 3,4 Diaminopyridine LGI1 30% B. Dronabinol C. Gabapentin • LGI1 – Is the main autoantigen of limbic encephalitis previously attributed to 13% 14% VGKCs D. Carbamazepine • 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 • e n i n t i Positive VGKCs but negative LGI1 and CASPR2 of debatable clinical d n p e y r i n a b i n o l a o b significance. a D r G
m i n o p • a Carbam azepine TAKE HOME: If neuromyotonia Check VGKC and CASPR2 D i , 4 (Many patients with neuromyotonia are negative for both VGKC and CASPR2) 3

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Neuromyotonia Treatments Patient Follow-Up
Symptomatic

Sodium Channel Blockers Initial diagnosis was stiff person syndrome

Carbamazepine, Phenytoin Referring Hospital


Miscellaneous Valium and IVIG prescribed no benefit

Dronabinol (cannabinoid) UCSF


Gabapentin Carbamazepine 400 mg twice daily marked improvement


PLEX additional improvement Immune

Outpatient – still symptomatic but not limited in his activities
In paraneoplastic form, removal of neoplasm usually
PLEX 1.5 plasma volume x 4, repeated monthly minimal effect
CBZ 400 mg three times daily
PLEX more effective than IVIG
Azathioprine 200 mg QD
Prednisone, azathioprine

Acknowledgements
Laura Rosow
Kaitlin Greene
Claire Clelland
Maulik Shah

Thanks for your attention!

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