Neurology Case Presentation August 31st, 2012 Dipika Aggarwal PGY 4 Neurology

Teen aged male admitted with acute onset generalized weakness for 1 day duration Woke up with diffuse weakness; no anti gravity strength in arms, unable to get out of bed Proximal > distal weakness; bilaterally symmetrical Denied diplopia, dysphagia, dysarthria, facial droop, drooling or change in level of consciousness

Denied any sensory complains Denied trouble breathing, urinary or bowel incontinence Denied any recent illness, trauma, travel or tick bite One episode of non-bloody emesis prior to admission

PMH: similar episode four months earlier, admitted to OSH for 4-5 days, ?? Diagnosed with GBS, ?? treated with plasmapheresis, no LP/ EMG PSH: none Home meds: None FH: HTN, migraine, DM, asthma, no similar problem in family members SH: denies smoking, ETOH or illicit drug use

Physical exam Vitals stable General physical exam unremarkable Neurological exam Mental status: AAO * 4 Speech : fluent with comprehension intact CN 2-12: PERRLA, EOMI, normal facial sensation and symmetry, normal facial strength, hearing intact, equal palatal elevation and tongue midline

Motor: Flaccid tone, motor strength 2/5 proximally and 3-4/5 distally BUE and BLE DTRs: Areflexic , toes downgoing Sensory: Intact to LT/PP/ Vibration and proprioception Unable to test for cerebellar function and gait

Where?? What??

Labs Hb - 14.6, WBC 6.1, Plt count 215 Sodium 143, K 1.3, Chloride 110, BUN 13, Creatinine 0.83, Glucose 151, Calcium 9.3, Magnesium 2.0, Phosphorus 2.4 CK 493, Aldolase 15.7 (on day 3) TSH: 2.082, free T3 – 3.8, free T4 – 0.9 Urine lytes: unremarkable

Hospital course Aggressive Potassium replacement Started showing improvement in muscle strength on day 1 By day 2 – strength was 5/5 BUE and BLE Diagnosed with familial hypokalemic periodic paralysis Discharged with follow up care with Jayhawk clinic

Muscle channelopathies Non dystrophic myotonias Myotonia congenita (CLCN1) Paramyotonia congenita (SCN4A) Sodium channel myotonias (potassium aggravated myotonias) (SCN4A) Periodic paralyses Hypokalemic (CACNA1S/ SCN4A) Hyperkalemic (SCN4A) Anderson Tawil syndrome (KCNJ2) The skeletal muscle genetic ion channelopathies are a distinct group of diseases caused by mutations which mainly occur in voltage-gated ion channel genes. They can be classified in to 2 categories – non dystrophic myotonias and periodic paralyses. NDMs are a group of conditions characterized by muscle stiffness on voluntary movement due to delayed skeletal muscle relaxation. This group includes - myotonia congenita, paramyotonia congenita and sodium channel myotonias (potassium-aggravated myotonias (PAMs), myotonia fluctuans, myotonia permanens and acetazolamide responsive myotonia.). The NDMs are mainly distinguished clinically from the dystrophic myotonias, myotonic dystrophy types 1 and 2, by the absence of extramuscular systemic involvement. The periodic paralyses are a group of autosomal-dominant disorders characterized by episodes of flaccid paralysis often triggered by an alteration in serum potassium concentration. They include – hypokalemic periodic paralyses type 1 and 2, hyperkalemic periodic paralysis and Anderson Tawil syndrome

Periodic Paralysis Secondary Hypokalemic: Thyrotoxic periodic paralysis hyperaldosteronism RTA villous adenoma cocaine binge diuretics, licorice, steroids, ETOH Hyperkalemic (k>7): hyporenemic hypoaldosteronism (DM/CRF) oral K, CRF, chronic heparin, rhabdomyolysis Normakalemic: Guanidine, sleep paralysis, MG, TIA, conversion

Hypokalemic periodic paralysis HypoKPP1 and 2 - CACNA1S/ SCN4A gene HypoKPP 1 is the most frequent form 1 in 100,000 Autosomal dominant inheritance pattern M:F – 3 or 4:1 Onset: first 2 decades of life HypoPP is associated with point mutations in both SCN4A and CACNA1S; however, approximately 10–20% of cases remain genetically undefined. Reduced penetrance in women

Clinical features Flaccid paralysis – mild focal weakness to severe generalized weakness Occur anytime of the day; more common in morning Absence of myotonia Proximal > distal weakness; legs > arms Sparing of facial, ventilatory and sphincter muscles Lasts several hours to more than a day Absence of clinical or electrophysiological myotonia is helpful in distinguishing this disorder from HyperKPP

Frequency: highly variable Frequency decreases after age 30; may become attack free in 40s and 50s Permanent fixed weakness or slowly progressive weakness more common with HypoKPP1 Attacks may be preceded by sensation of heaviness and or aching in the low back Frequency: several times a week to less than once a year Permanent weakness more common with HypoKPP 1 as compared to type 2

Precipitating factors Strenuous physical activity followed by rest or sleep High carb diet ETOH consumption Emotional stress Concurrent viral illness Lack of sleep Medications like beta agonists, corticosteroids, and insulin Often a first attack occurs in a teenager who has participated in a sporting event and celebrated afterward with pizza and beer or soda

Hypokalemic Periodic Paralysis Genetics Mutations in voltage sensor segment D2S4 of 1 subunit of skeletal muscle Ca channel gene, chromosome 1q Arg528His, Arg1239His, Arg1239Gly Less commonly SCN4A mutation enhances Na inactivation About 70% cases of familial HypoKPP are ass.with mutations in the a subunit of the skeletal muscle Ca channel located on chr 1. The calcium channel is composed of 5 subunits – a1, a2, b, gamma and delta. The a1 subunit is composed of 4 domains, each containing 6 transmembrane segments S1-6 containing the DHP. This receptor functions not only as a cal channel but also as a voltage sensor for E-C coupling. The S4 segment of the a1 subunit confers voltage sensing properties to the channel and is the site of most common mutation. The mutations occur in highly conserved arginine residues in the voltage sensing segments of the calcium channel. Less commonly ~10% mutations are seen in a subunit of skeletal muscle sodium channel gene

Hypokalemic Periodic Paralysis Pathophysiology The mutation slows the activation rate of L-type Ca current to 30% of NL Reduced RYR1-mediated Ca release from SER Reduced calcium current density Impaired E-C coupling ? role of K and ? inexcitability Ca homeostasis change reduces ATP-dependent K channel current and leads to abnormal depolarization (Tricarico D et al 1999) Now we know that there is a mutation in the skeletal muscle ca channel which slows the rate of channel activation and therefore ca influx. As mentioned earlier this receptor also acts as a voltage sensor leading to reduced ryanodine receptor medicated ca release from the SER leading to reduced calcium current leading to impaired E-C coupling. The exact role of hypokalemia is not well understood. As with other forms of paralysis, muscle fibres are depolarized and inexcitable during the attack. In vitro, muscle fibres from pts with hypoKPP exposed to low K shows paradoxical depolarization. Hence hypothesizing that cal channel mutation leads to changes in calcium homeostasis which reduces ATP dependent K current creating a hypokalemic state which leads to abnormal depolarization. One of the theories α subunit of the voltage-gated calcium channel, Cav1.1 (also known as the skeletal muscle L-type calcium channel, and the dihydropyridine receptor HypoPP is most commonly associated with mutation of CACNA1S (type I HypoPP), which encodes the α subunit of the voltage-gated calcium channel, Cav1.1 (also known as the skeletal muscle L-type calcium channel, and the dihydropyridine receptor). Cav1.1 in the T-tubular membrane is attached to the ryanodine receptor of sarcoplasmic reticulum, for which it acts as a voltage sensor. About 10% of HypoPP is associated with mutations in SCN4A (type 2 HypoPP), which encodes the skeletal muscle sodium channel.

Diagnostic studies Serum K < 3.0mEq/L Serum CK level elevated EKG changes – U waves, flattening of T waves Provocative testing - Intravenous glucose load/ insulin Electrophysiology Sensory and motor NCS normal between attacks During attacks – small CMAP. Reduced insertional activity, fibs and positive sharp waves No myotonia on EMG Short/ long exercise test Serum K < 3.0mEq/L during the attack; normal in between Provocative testing using Intravenous glucose load/ and sometimes insulin in order to lower the serum K – used in past electrocardiographic (ECG) signs of hypokalemia (U waves in leads II, V-2, V-3, and V-4, progressive flattening of T waves and depression of ST segment) NCV & EMG during attacks CMAP amplitudes: Small Insertional activity: Reduced Spontaneous activity: Fibrillations; Positive sharp waves Motor unit potentials: Increased polyphasia

Periodic Paralysis Muscle Pathology Muscle biopsy reserved to atypical patients with normal provocative and gene testing Vacuoles reflect permanent myopathy Vacuoles represent proliferation, degeneration and autophagic destruction of T-tubules & SR Large central vacuoles in hypokalemic PP Muscle biospy reveal intracellular vacuoles which reflect proliferation, degeneration and autophagic destruction of the T tubules and SR. Large central vacuoles are more likely to be asso.with HypoKPP 1 and tubular aggregates are more common with HypoKPP 2

Hypokalemic Periodic Paralysis Pathology early in course, during attacks of weakness: Internal vacuoles with amorphous debris Occasional tubular aggregates

Treatment Reducing exposure to known triggers Acute treatment – replacement of K Acetazolamide – prevent attack recurrence and severity Acetazolamide may ppt weakness in HypoKPP2 Dichlorphenamide – no longer available Triamterene and spironolactone

Diagnosing Muscle Channelopathies R/O secondary forms Measure K+ during attack Provocative testing for PP: seldom done! Hypo: gluc/insulin Hyper: K+ Muscle Bx – vacuoles/dilated T-tubules Electrophysiology EMG Short/long exercise tests Genetics

Electrophysiology: Short Exercise Test More useful in MC Baseline CMAP Exercise 10 sec Record CMAP immediately post exercise, then q 10 sec for 1 min.  CMAP in MC and PMC PMC exacerbated by cold No change in CMAP in HypoKPP The short exercise test was originally described by Streib and colleagues (1982) investigating patients with myotonia. The technique involves a short period (10 s) of isometric contraction of one of the small hand muscles ADM followed by CMAP monitoring every 10 s usually up to one minute. In normal individuals a transient small increase in CMAP amplitude may be observed (Streib et al., 1982, Fournier et al., 2004). The short exercise test has been found helpful in the evaluation of patients with myotonia congenita where a transient decrease in CMAP amplitude mirrors the transient weakness elicited clinically (Streib et al., 1982, Fournieret al., 2004). In paramyotonia congenita there is a decrease in CMAP following exercise which is exacerbated or may only become apparent after cooling Patients with hypokalemic periodic paralysis showed no abnormalities in the short exercise test. (Streib. Musc. Nerve. 1982; 5: 719-723) (Fournier. Ann. Neurol. 2004; 56: 650-661) (Fournier Neurology 2009)

Long Exercise Test for Periodic Paralysis Record ulnar CMAP Amp baseline Exercise ADM 5 min Check CMAP every 2 min. for 50 min In PP (all types),  Amp immed post ex, over next 10-40 min, grad dec amp In MC ↓ Amp immed post ex, rapid return to baseline In PMC sustained ↓ Amp McManis et al. introduced the long exercise test in 1986 (McManis et al., 1986). This involves sustained maximal isometric exercise for 2–5 min (with a short rest period every 15–30 s) in one of the small hand muscles (typically abductor digiti minimi; ADM) with CMAP monitoring every 1–2 minutes during and after the exercise for approximately 30–40 minutes or until no further decrement occurs. In pts with PP, an immed increase in CMAP is observed followed by a delayed CMAP amplitude decline over the next 10-40 mins. Decline is greater and more frequently seen in patients with hyperPP compared to hypoPP. Whereas in pts with MC and PMC there is a immed decline in CMAP with rapid return to baseline. CMAP amplitude Increased immediately after sustained (5 min) maximal contraction Progressively reduced (by 40%) during rest 20 to 40 min after initial increment (80% of patients) Normals: Mild increase in CMAP amplitude after exercise Epinephrine reduces size of CMAP (McManis. Musc. Nerve. 1986; 9: 704-710) (Fournier. Ann. Neurol. 2004; 56: 650-661)

References Dr.Barohn’s presentation on “Muscle Channelopathies” Anthony A.Amato and James A.Russell; Non dystrophic myotonias and periodic paralysis. Neuromuscular disorders 2008, Mc Graw Hill, Section II Chapter 29; 655-680 Burge JA, Hanna MG. Novel insights into the pathomechanisms of skeletal muscle channelopathies; Curr Neurol Neurosci Rep. 2012 Feb Vol 12:62-69 Hanna, Dipa L Raja Rayan and Michael G. Skeletal Muscle Channelopathies:Non Dystrophic Myotonias and Periodic Paralysis. Current Opinion in Neurology, 2010 Vol. 23: 466-476 neuromuscular.wustl.edu Doreen Fialho and Michael G.Hanna. Periodic paralysis, Handbook of Clinical Neurology, 2007 Vol. 86 (3rd series), p 89-90