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

2. 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

3. 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

4. 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

5. 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

6. 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

7. Where??
What??

8. Labs
Hb , 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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.

18. 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

19. 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

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

21. 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

22. 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

23. 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: )
(Fournier. Ann. Neurol. 2004; 56: ) (Fournier Neurology 2009)

24. 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 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 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: )
(Fournier. Ann. Neurol. 2004; 56: )

25. 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;
Burge JA, Hanna MG. Novel insights into the pathomechanisms of skeletal muscle channelopathies; Curr Neurol Neurosci Rep 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:
neuromuscular.wustl.edu
Doreen Fialho and Michael G.Hanna. Periodic paralysis, Handbook of Clinical Neurology, 2007 Vol. 86 (3rd series), p 89-90