Neurology Case Presentation Dr. M. A. Sofi MD; FRCP (London): FRCPEdin; FRCSEdin

Case history 19 year old 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

Case history PMH: similar episode in Feb 2013, admitted to local hospital for 4-5 days, ?? Diagnosed with GBS, ?? treated with plasmapheresis, no LP/ EMG PMH: nil significant Home meds: None FH: Nil for 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 * 3 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

Case history Motor: Flaccid tone, motor strength 2/5 proximally and 3-4/5 distally BUE and BLE DTRs: Normal , planter both down going Sensory: Intact to LT/PP/ Vibration and proprioception Unable to test for cerebellar function and gait

Case scenario What is the clinical pattern of weakness? What is the anatomical localization? What is the differential diagnosis?

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 electrolytes: 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

Paramyotonia congenita Sodium channel myotonias Muscle channelopathies 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 Sodium channel myotonias (potassium-aggravated myotonias (PAMs) Myotonia fluctuans Myotonia permanens Acetazolamide responsive myotonia

Muscle channelopathies 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 HypoPP is associated with point mutations in both SCN4A and CACNA1S; however, approximately 10–20% of cases remain genetically undefined. Reduced penetrance in women 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 Absence of clinical or electrophysiological myotonia is helpful in distinguishing this disorder from HyperKPP 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

Effects of hypokalaemia on the ECG Changes appear when K+ falls below about 2.7 mmol/l Increased amplitude and width of the P wave Prolongation of the PR interval T wave flattening and inversion ST depression Prominent U waves(best seen in the precordial leads) Apparent long QT interval due to fusion of the T and U waves (= long QU interval)

Hypokalemic periodic paralysis 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

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

Treatment Reducing exposure to known triggers Acute treatment – replacement of K Acetazolamide – prevent attack recurrence and severity Acetazolamide may ppt weakness in HypoK PP2 Dichlorphenamide – no longer available Triamterene and spironolactone

A 38-year-old man, feeling poorly after finishing a marathon, was brought to the medical tent near the finish line. He had run three marathons in the past two years. He was confused, but not hypotensive; pulse was 130 beats/min; his weight was 4.5 kgm higher than at the start of the race. Electrolyte measurements on site included a serum sodium concentration of 118 mEq/L. The most likely proximate reason for the hyponatremia is: Cerebral salt wasting NaCl-wasting nephropathy Excessive intake of hypotonic fluid Excessive sweating

A 60-year-old man with known lung cancer is seen in follow-up with no major symptomatic changes. His BP is 150/90 mmHg, pulse 86 and regular and he has no edema. Electrolytes reveal a serum sodium concentration of 125 mEq/L; BUN is 6mg/dl, uric acid is 2.8 mg/dl, and the urine osmolality is 280 mosm/kg. The most likely explanation for the hyponatremia is: Cerebral salt wasting Diuretic use/abuse SIADH Psychogenic polydipsia

The most appropriate therapy for patient #2 is: Solute-free water restriction DDAVP Cortisone 5% hypertonic saline

60 Year old presented with recurrent attacks of syncope What does ECG rhythm strip show? _______ What treatment is recommended? ________

67 year old man presented with left side hemiplegia Describe CT finding? ___ What vascular territory is involved? _____

Presented with severe acute pain inability to move foot. What is the diagnosis? _________ What blood test has diagnostic value? _______________

Name 2 abnormalities of blood gas analysis above? ___________ A 65 year-old man with severe dyspnoea. The patient has a history of Chronic Obstructive Airway Disease (COAD), with regular use of bronchodilators. He is still a heavy smoker, but has no other relevant past history. Upon arrival, arterial blood gases are taken (on 12L / min of O2): pH 7.15 (7.35 – 7.45) PO2 80 mmHg (80 – 95) PCO2 95 mmHg (35 -45) HCO3 42mmol/L (22 – 28) Base Excess + 17 (-3 - +3) SaO2 90% On arrival, he is sweaty, distressed and peripherally cyanosed Vital Signs: RR 45/min intercostal recession Tempt 38 deg C BP 180/90 mmHg Name 2 abnormalities of blood gas analysis above? ___________

THANK YOU

History 31yo F w/several months progressive BLL weakness; pain greater in LLE Bilateral numbness just above breasts & inferiorly Muscle aches cramps spasms falls Urinary incontinence & saddle anesthesia Constipation 2wks (manual dis-impaction) No history of spinal operation or trauma No F/C/N/V

Physical Exam Sensory deficit inferior to T1 bilaterally Decreased rectal tone Motor: LLE 2/5, RLE 5/5 Increased tone/spasticity Hyper-reflexia Babinski: Bilateral up going toes Gait: Able to stand with assistance; drags LLE, circumduction

Localization What are the major symptoms and clinical findings ? What is the anatomical localization of the lesion? What is the differential diagnosis? What investigation are requested?

Sag T1 FS MRI Post Sag T2 MRI T2: Hyperintense lesion with widening of the spinal cord; led to radiographic diagnosis of tumor. “Since demyelinating disease is in the differential of spinal cord lesions, CSF was sent.

Labs/CSF Gram stain & culture: rare monocytes, no organisms isolated CSF glucose: 69 CSF protein: 31 Elevated levels of IgG antibodies Oligoclonal bands: negative

Differential Diagnosis Tumor Astrocytoma Ependymoma Demyelinating lesion: Multiple sclerosis Neuromyelitis optica Transverse myelitis ADEM

Inflammatory Demyelinating Lesion: H&E photomicrographs showing (clockwise) hypercellular neural tissue, vessel with perivascular lymphocytic inflammation, abnormal vessel with probable chronic inflammation, and intact neurons. H&E Stain Hypercellular neural tissue, vessel with perivascular lymphocytic inflammation.

Diagnosis Inflammatory demyelinating lesion Multiple Sclerosis No further surgical intervention Neurology for management of MS Follow up in clinic 2 months postop Motor LLE improved MRI Brain & C-spine

Multiple Sclerosis Relapsing-remitting MS (RRMS): Most common 85% of MS initially diagnosed Partial or total recovery between attacks Secondary-progressive MS (SPMS): RRMS course, but becomes gradually progressive Attacks & partial recoveries may continue to occur Over 60% initially RRMS progress to SPMS in 10 yrs MBP: 3.64 NMO-IgG serum negative (aquaporin 4, neuromyelitis optica; sent 1mo) CSF: 24 lympho, 1 macro; glu 54; prot 32 Immunoelectrophoresis; nml serum and csf proteins Protein electrophoresis: Paraprotein M-spike not present

Multiple Sclerosis Primary-progressive MS (PPMS): Progressive from onset Symptoms generally do not remit Progressive disability w/o acute attacks 15% of MS initially diagnosed Primary-relapsing MS (PRMS): Same as PPMS, but with acute attacks

Multiple Sclerosis Clinical: Episodic, relapsing-remitting neurologic symptoms in a young adult (typically) Neurological symptoms disseminated in time & space Common presentations: monocular visual disturbances (optic neuritis), paresthesias/weakness (myelitis), incoordination (cerebellar), and/or diplopia (brainstem) Labs: Oligoclonal bands positive, MBP elevated Not specific, new tests improving sensitivity/specificity Early MS vs Clinically definite MBP elevated in various disease processes MRI: T2 intense foci in white matter (UBOs), juxtacortical (G-W junction involving U-fibers), periventricular lesions, involve corpus collosum (perpendicular extensions) Unidentified bright objects

For dissemination in space (DIS) lesions in two out of four typical areas of the CNS are required: Periventricular Juxtacortical Infratentorial spinal cord

For dissemination in time (DIT) there are two possibilities: A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI OR Simultaneous presence of asymptomatic gadolinium-enhancing and non-enhancing lesions at any time

ADEM ADEM)is another important differential diagnosis of MS. This is a monophasic, immune-mediated demyelinating disease which often presents in children following an infection or vaccination. On MRI there are often diffuse and relatively symmetrical lesions in the supra-and infratentorial white matter which may enhance simultaneously. There almost always is preferential involvement of the cortical gray matter and the deep gray matter of the basal ganglia and thalami. Here we have axial FLAIR and T2W-images of a young patient with ADEM - notice the extensive involvement of the cortical and gray matter, including thalamus.

Tumefactive MS Tumefactive demyelinating lesion (TDL) is defined as a solitary de-myelinating lesion greater than 2 cm. Mass effect and contrast enhancement on neuroimaging make it difficult to distinguish this type of lesion from high-grade gliomas

Tumefactive MS This patient was a previously healthy 35-year-old woman who presented with new-onset generalized tonic-clonic seizures and headaches. MRI scans showed a large right frontal mass with surrounding edema and a mild midline shift. The patient underwent a diagnostic stereotactic brain biopsy. Low-grade glioma and reactive gliosis were among the likely differential diagnoses. Permanent section showed a demyelinating lesion. T1-weighted magnetic resonance imaging scan showed a right frontal lesion with midline shift.

Neuromyelitis Optica This is a demyelinating disease in which the optic nerves and spinal cord are usually involved. Often there are few T2-lesions in the brain. Think of NMO when there are extensive spinal cord lesions (more than 3 vertebral segments) with low T1-signalintensity and swelling of the cord. On axial images the lesions often involve most of the cord. This is unlike MS, in which the lesions are usually smaller and peripherally located. The clue to the diagnosis is in the AQP4-AB titer 1:1024.

Borderzone infarction typically these lesions are located in only one hemisphere, either in deep watershed area or peripheral watershed area. ADEM Multifocal lesions in WM and basal ganglia 10-14 days following infection or vaccination. As in MS, ADEM can involve the spinal cord, U-fibers and corpus callosum and sometimes show enhancement. Different from MS is that the lesions are often large and in a younger age group. The disease is monophasic.

Lyme 2-3mm lesions simulating MS in a patient with skin rash and influenza-like illness. Other findings are high signal in spinal cord and enhancement of CN7 (root entry zone). Sarcoid Sarcoid is the great mimicker. The distribution of lesions is quite similar to MS.

PML PML is a demyelinating disease caused by JC virus in immunosuppressed patients. space-occupying, nonenhancing WMLs in the U-fibers (unlike HIV or CMV). PML may be unilateral, but more often it is asymmetrical and bilateral. Virchow Robin spaces Bright on T2WI and dark on FLAIR. Small vessel disease WMLs in the deep white matter. Not located in corpus callosum, juxtaventricular or juxtacortical. In many cases there are also