Myotonic Dystrophy/CIDP

From the Northern New England Neurological Society’s Annual Meeting, presented by the
Northern New England Neurological Society and the University of Vermont College of Medicine

Educational Objectives

The goal of this program is to improve the diagnosis and management of dystrophia myotonica (DM) and chronic in­flammatory demyelinating polyneuropathy (CIDP). After hearing and assimilating this program, the clinician will be better able to:

1.   Explain the genetic causes of DM

2.   Distinguish DM type I from DM type II.

3.   Manage the patient with DM using yearly screens for associated complications, physical and occupational therapy, and genetic counseling.

4.   Use nerve conduction studies and sural nerve biopsies to diagnose CIDP and distinguish it from other demye­linating disorders.

5.   Optimize treatments to prevent disease progression and disability in patients with CIDP.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Tandan is on the Speakers’ Bureau for Talecris Biotherapeutics.  Dr. Cohen and the planning committee reported nothing to disclose.  In his lecture, Dr. Tandan presents information that is related to the off-label or investigational use of a therapy, product, or device.

Myotonic Dystrophy

Jeffrey A. Cohen, MD, Professor of Neurology, Dartmouth Medical School; Section Chief of Neurology, Dart­mouth Hitchcock Medical Center, Hanover, NH

Background on dystrophia myotonica (DM): multisystem myotonic myopathy; classified into 2 types (caused by distinct genetic mutations); dystrophia myotonica type I (DM1)  —most prevalent inherited neuromuscular disease in adults; autosomal dominant; variable penetrance; subject to anticipation (ie, disease worsens in every new gener­ation); dystrophia myotonica type II (DM2)  —  myopathies typically present proximally; DM presents distally at first, but DM2 often affects proximal muscles; typically seen in European families; has less severe presentation (compared to DM1)

Genetics: DM1  —  caused by trinucleotide repeat in intron segment of dystrophia myotonica protein kinase (DMPK) gene on chromosome 19; testing allows classification based on number of repeats; effects of DMPK mutation  —  defective DMPK in cardiac and skeletal muscle; possible disruption of transcription in neighboring genes (eg, mes­senger-ribonucleic acid splicing of chloride channel protein 1 [CLC1]); DM2  —  caused by mutation in normal re­peat sequence of zinc finger protein 9 gene (75 to 11,000 repeats possible, but patients average 5,000); anticipation in DM1  —  parents often mildly affected; successive generations develop more severe forms; exacerbated by female transmission; classification groups and nucleotide repeats in DM1  —  1) minimally affected or asymptomatic carri­ers (50-100 repeats), 2) classical adult onset (100-700), 3) severe congenital onset (>700)

Characteristics of DM1: muscle stiffness  —  repetitive muscle contractions caused by trains of repetitive action po­tentials (response to contraction); muscle weakness and wasting  —  neck extensor weakness (rare condition) also seen in amyotrophic lateral stenosis [ALS] and myasthenia gravis); isolated cervical myopathy; extensors in toes and feet; hands (seen before proximal weakness); diaphragm and intercostal muscles; palatal and pharyngeal mus­cles in tongue (may cause obstructive sleep apnea [OSA] as early symptom; history should include detailed screen­ing [eg, ask about headaches on awakening and frequent recall of dreams]); extraocular muscles (may cause ptosis); myotonic grip  —  slow opening of hand after tight grip; improves after repeated attempts (warm-up phenomenon); test on thenar eminence (thumb should rise) and tongue (eg, percussion myotonia after tapping with tongue blade); other symptoms  —  "Christmas tree cataracts"; testicular atrophy; insulin resistance (often progresses to type 2 dia­betes); pituitary problems; hyperparathyroidism; frontal balding; cardiac conduction defects; congestive heart fail­ure; cardiomyopathy; respiratory insufficiency gastrointestinal (GI) issues (presenting complaint in »30% of patients; eg, constipation or diarrhea); cognitive impairment; mental retardation; patients often share similar physi­cal appearance

Congenital DM: symptoms in infancy  —  hypotonia; difficulty with respiration and feeding; undescended testes; skel­etal deformities; respiratory distress; mother may have difficulties during pregnancy; prognosis  —  IQ of 40 to 80; delayed developmental milestones; behavioral abnormalities (eg, severe underactivity or hyperactivity); classic symptoms of DM appear by adolescence; facial appearance  —  tenting of mouth; distinct stare; drooling

Characteristics of DM2: older age of onset (³30 yr); nonspecific symptoms (eg, proximal presentation with less cra­nial nerve involvement); cardiac arrhythmias; endocrinopathies; hearing loss; cataracts (common); prominent hy­perhidrosis (distinguishes DM2 from DM1); calf hypertrophy (extremely common and obvious); iron accumulation (rare)

Diagnostics: family history  —  important; testing grip and relaxation in family members critical; serum  —  creatine ki­nase (CK) often elevated, but may be normal; electromyography (EMG)  —check for "dive bomber" potentials; ge­netic screening  —  use specific tests (DM2 distinct from DM1); EMG motor unit potentials  —  low amplitude; short duration; recruit quickly (as opposed to isolated motor units); distal muscles have combination of neuropathic and myopathic signs; proximal muscles (eg, deltoid, biceps) show obvious myotonia; muscle biopsy  —   shows long strings of nuclei (“tram tracking”); central nuclei (less specific to DM)

Differential diagnosis: DM2  —  calf hypertrophy; DM1  —cataracts; percussion myotonia; inability to relax; frontal baldness (in men); in women, obtain history of pregnancies; process  —  rule out other causes of myotonia and neu­romyotonia (eg, inflammatory myopathy, acid maltase deficiency, chloride channel myopathy, sodium channel myotonia); muscle biopsy not typically required; hyperkalemic periodic paralysis  —distinguished by episodic symptoms; may present with unusual insertional or spontaneous activity, neuromyotonia, or other discharges on EMG, but lacks clear dive bomber potentials seen with DM; myotonia congenita  —  shows only limited weakness; inclusion body myositis  —  causes weakness in finger extensors, wrist flexors, and quadriceps and bilateral foot drop; associated with serum CK of 500 to 600 U/L; typically seen in older patients; spares cranial musculature; may cause severe respiratory problems or peripheral neuropathy; diagnosed with biopsy; limb-girdle muscular dystrophy  —  “wastebasket” label for collection of disorders; inflammatory myopathies  —  uncommon

Distinguishing DM1 from DM2: onset  —  DM1 may present at any age, but DM2 presents in older patients; anticipation  —  seen with DM1, but rare with DM2; cranial involvement  —  DM1 may cause severe symptoms (eg, difficulty with eating and swallowing, tongue weakness, dribbling); calf hypertrophy  —  limited to DM2; cataracts  —  DM1 and DM2; balding  —  DM1 and DM2 (less prominent in DM2); endocrinopathies  —  DM1 and DM2 (significantly greater prevalence in DM1); cognitive dysfunction  —limited to DM1; DM2 may be associated with unique personality traits and mild cognitive impairment; hyperhidrosis  —  seen with DM2, but rarely seen with DM1

Treatment and management: successful treatments remain unavailable; conduct yearly screens for associated com­plications (eg, electrocardiography, cardiology consultation); pacemaker placement may be required (deaths due to stroke rare, but speaker reports cardiac deaths and pulmonary deaths due to recurrent aspirations and respiratory failure); check for diabetes, hypogonadism, and increased follicle-stimulating hormone; cataracts  —  treatment greatly improves patient's lives; peripheral neuropathy plus impaired visual acuity creates significant risk for falls; other testing  —  pulmonary function tests; polysomnography (to rule out OSA); physical therapy and occupational therapy  —  recommended; genetic counseling  —  critical; many families lack understanding of DM's reproductive conse­quences; pregnant patients should consult high-risk pregnancy counselor; GI  —patients show dysmotility problems; OSA  —  speaker recommends modafinil; congenital DM  —  assess for failure to thrive

Anesthesia concerns: difficulty awakening or weaning from ventilator; dislocations during intubation; need for extra monitoring; hypersensitivity to opiates; increased risk for postoperative pneumonia; always warn surgeons about patient's DM, even for minor procedures

Contraindicated medications: amitriptyline; neuroleptics; propranolol

Chronic Inflammatory Demyelinating Polyneuropathy

Rup Tandan, MD, Professor of Neurology, University of Vermont College of Medicine,  and Attending Neurolo­gist, Fletcher Allen Health Care, Burlington, VT

Distinguishing clinical features of chronic inflammatory demyelinating polyneuropathy (CIDP): progression of deficits over ³2 mo; weakness shows greater prominence than sensory symptoms; symmetric involvement (hall­mark); some patients have both proximal and distal involvement, but some show only proximal involvement; re­duced and frequently absent reflexes in limbs; increased cerebrospinal fluid (CSF) protein; nerve conduction studies (NCS) show primarily acquired multifocal demyelinating neuropathy; nerve biopsy shows segmental demy­elination (with or without inflammation) and remyelination

Diagnostic criteria: prevalence  —  differences in prevalence may be due to choice of criteria; American Academy of Neurology (AAN) criteria most stringent, so resulting prevalence lowest; Inflammatory Neuropathy Cause and Treatment (INCAT) criteria least stringent (highest prevalence); increased in males (3-6 fold); increases with age; electrophysiologic criteria  —  primary demyelination; conduction block; temporal dispersion; if conduction block not present, other features of demyelination must be confirmed (eg, temporal dispersion, prolonged motor response, prolonged distal latency, slowing of conduction velocity, prolongation of F waves); electrophysiologic criteria can­not reliably distinguish CIDP from hereditary demyelinating neuropathies

Diagnostic testing: sensory NCS  —  valuable; sural response typically spared in patients with CIDP; sensory ratio (su­ral plus radial sensory nerve action potential [SNAP] amplitude divided by median and ulnar SNAP amplitude) of >1 suggests CIDP; median response often absent; nerve biopsy findings  —large segments of absent myelin visible after staining (teased fiber analysis); "onion bulbs" (ie, unraveling of Schwann cell cytoplasm around thinly my­elinated axons; suggests repeated demyelination and remyelination); patients with clinical signs of CIDP may not show direct evidence on nerve biopsy, but staining of cells typically reveals elevated numbers of T-cell and B-cell markers and macrophages; edema often present in nerve (associated with inflammation)

Nerve biopsy: in studies, only 11% to 50% of patients show inflammation; thus, inflammation not universal in CIDP (if only examining hematoxylin and eosin stained sections for inflammatory nerve infiltrates); demyelination and remyelination  —  possibly more sensitive as indicator of CIDP (found in 50%-70% of patients); inflammatory cells  —  typically CD68+ macrophages; CDA+ T cells exceed CD4+ T cells; sural nerve biopsy (SNB)  —  1 study found no diagnostic value, but another study found SNB essential and relevant in £68% of patients; in speaker's findings, corrected criteria gave SNB greater sensitivity than electrophysiologic testing (SNB from £90% of pa­tients with suspected CIDP who did not have all other criteria met histologic criteria for demyelinating neuropa­thy); conclusions  —  nerve biopsy not essential; consider biopsy if CIDP suspected clinically but EMG inconclusive; useful for ruling out related disorders (eg, amyloid disease); targeted fascicular ventral rootlet biopsy  —  new type of biopsy; SNB examines distal sensory nerve, but CIDP is proximal motor disorder

Other immune-mediated demyelinating neuropathies: acute inflammatory demyelinating polyneuropathy (AIDP)  —  typ-ically <4-wk period of progression (CIDP has ³8 wk progression); subacute inflammatory demyelinating polyneuropathy  —  4 to 8 wk of progression; characteristics  —  some patients have self-resolving disorders; other pa­tients have chronic disorders (eg, CIDP) and require treatment; acute CIDP  —  many patients with acute inflamma­tory disorders (eg, infection plus weakness) improve after intravenous immunoglobulin (IVIG) or plasmapheresis, but worsen again in »4 wk; these patients may have acute CIDP (indistinguishable from Guillian-Barre syndrome [GBS]); acute CIDP not monophasic, progresses to relapsing-remitting disease, and responds to corticosteroids or IVIG; features suggesting AIDP  —  preceding infectious illness (however, one-third of patients with CIDP also have acute illness before symptoms); facial weakness; autonomic involvement; respiratory failure

Magnetic resonance neurography: new diagnostic tool; patients with chronic disorders show significant enlarge­ment of brachial plexus and pelvic nerves (indicating massive demyelination and remyelination or potato-shaped swellings of myelin)

Diagnostic algorithm: if progressive or relapsing proximal and distal weakness presents without significant sensory loss and tendon reflexes for duration <4 wk, evaluate electrophysiology and consider diagnosis of GBS; if duration >8 wk, assess EMG for signs of demyelination; treat for CIDP if EMG shows demyelination and CSF shows in­creased protein with no cells; family history critical (patients with relevant family history unlikely to have CIDP; hereditary disorders show 2-fold greater prevalence)

Treatment decisions: patients with unequivocal evidence of CIDP require aggressive treatment with immune-based therapy; suspected CIDP  —  no guidelines for trial treatment with IVIG or corticosteroids; sensory CIDP  —  treatment decisions difficult due to absence of objective index; speaker's recommendations  —  try corticosteroids if uncertain about diagnosis or treatment; discuss exit strategies with patients (in case side-effects develop)

Treatments: first-line therapies  —  prednisone; IVIG; plasmapheresis; dexamethasone vs prednisolone study  —  no dif­ferences found; case reports  —  improvement seen with rituximab and alemtuzumab (consider for patients with refractory symptoms or intolerance to first-line agents); selecting first-line therapy  —often depends on external factors, (eg, in­surance coverage, available facilities); no evidence for superiority of any treatment; IVIG gaining popularity due to favorable side effect profile and rapid effects; plasmapheresis often reserved for patients with severe symptoms, re­lapses, or lack of response to IVIG and corticosteroids;  efficacy  —  prednisone (80%-90%); IVIG (»66%); plasma­pheresis (80%); side effects  —IVIG and plasmapheresis not typically associated with major side effects; however, speaker has seen some serious reactions, and increasingly uses IVIG

Large IVIG study: 48 wk; IVIG given at starting dose of 2 g/kg for 2-4 days, then maintenance dose of 1 g/kg every 3 wk; at 24 wk, twice as many patients receiving IVIG responded than those on  placebo; at 48 wk, relapse rate 3 times greater in placebo group and relapses earlier and longer than in IVIG group; 87% of patients on IVIG and 55% of placebo group had no relapses; maximum improvements seen after 16 to 20 wk or longer; improvement continues up to 32 wk, then plateau seen

Immunization safety study: relapses increased after vaccinations for influenza (4%), tetanus (8%), and pneumococ­cus; caution recommended when using tetanus toxoid; overall relapse rate 8%, but symptoms typically mild; Neth­erlands study  —  2 of 76 patients developed both GBS and CIDP after influenza vaccination; recurrent vaccinations increased relapses in selected patients; speaker's advice  —  vaccinations recommended; risk for severe relapse trig­gered by infection (eg, influenza) outweighs risk for mild relapse from immunization

IVIG failure: no clear definition or guidelines; specialists recommend attempting 2 to 4 monthly courses before dis­continuation

Conclusions: early detection and treatment of CIDP may prevent disease progression due to demyelination and sec­ondary axonal loss; treatment intervals must be optimized to prevent deterioration (3 wk used in study); long-term therapy required to maintain response and establish remission

Acknowledgments

Drs. Cohen and Tandan were recorded at Northern New England Neurologic Society Annual Meeting, held October 22-23, 2010, in Burlington, VT, and sponsored by the University of Vermont College of Medicine and Fletcher Allen Health Care. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Suggested Reading

Bhakta D et al: Increased mortality with left ventricular systolic dysfunction and heart failure in adults with myotonic dys­trophy type 1. Am Heart J 160:11, 2010; Bril V et al: Electrophysiologic correlations with clinical outcomes in CIDP. Mus­cle Nerve 42:492, 2010; Conravey A, Santana-Gould L: Myotonia congenita and myotonic dystrophy: surveillance and management. Curr Treat Options Neurol 12:16, 2010; Gagnon C et al: Health supervision and anticipatory guidance in adult myotonic dystrophy type 1. Neuromuscul Disord 20:847, 2020; Kulkarni GB et al: Sural nerve biopsy in chronic in­flammatory demyelinating polyneuropathy. Neurol India 58:542, 2010; Mahdi-Rogers M et al: Immunomodulatory treat­ment other than corticosteroids, immunoglobulin and plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev 11:CD003280, 2010; Orlikowki D et al: Modafinil for the treatment of hypersomnia associated with myotonic muscular dystrophy in adults. Clin Ther 31:1765, 2009; Raheem O et al: Mutant (CCTG)n expansion causes abnormal expression of zinc finger protein 9 (ZNF9) in myotonic dystrophy type 2. Am J Pathol 177:3025, 2010; Rigas M et al: Safety of liquid intravenous immunoglobulin for neuroimmunologic disorders in the home setting: a retrospective analysis of 1085 infusions. J Clin Neuromuscul Dis 10:52, 2008; Schoser B, Thimchenko L: Myo­tonic dystrophies 1 and 2: complex diseases with complex mechanisms. Curr Genomics 11:77, 2010; Sinclair JL, Reed PW: Risk factors for perioperative adverse events in children with myotonic dystrophy. Paediatr Anaesth 19:740, 2009.