Highlights from the Northern New England Neurological Society Annual Meeting

Presented by the University of Vermont College of Medicine in alliance with Fletcher Allen Health Care

Educational Objectives

The goals of this program are to improve the diagnosis and treatment of Dravet syndrome and to improve the practice of acupuncture. After hearing and assimilating this program, the clinician will be better able to:

1.   Use clinical presentation, electroencephalography, and genetic testing to diagnose Dravet syndrome.

2.   Counsel families about the genetics and molecular mechanisms of Dravet syndrome.

3.   Choose the appropriate treatment for patients with Dravet syndrome.

4.   Assess the data supporting the beneficial effects of acupuncture for treatment of chronic conditions and elabo­rate on the potential role of nonspecific placebo effects.

5.   Educate patients about the latest research into possible physiological mechanisms associated with acupuncture and recommend whether acupuncture therapy appears appropriate for individual patients.

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 faculty and the planning committee re­ported nothing to disclose. In his lecture, Dr. Morse presents information related to the off-label or investigational use of a therapy, product, or device.

Dravet Syndrome

Richard P. Morse, MD, Associate Professor of Pediatrics and Neurology, Dartmouth Medical School; Chief, Child Neurology and Development, Dartmouth-Hitchcock Medical Center, Hanover, NH

Background: previously known as severe myoclonic epilepsy of infancy (SMEI); affects »1 in 40,000 children and accounts for »7% of severe epilepsy in children <3 yr of age; genetic testing may establish higher prevalence; part of spectrum of generalized epilepsy with febrile seizures plus (GEFS+); children 10 to 15 yr of age remain suscep­tible to development of hyperthermia-induced seizures; genetics  —  families with GEFS+ who did not have persis­tent epilepsy with cognitive impairment have mutations in subunit type B of sodium channel; some families have members who have GEFS+ and Dravet syndrome and have mutations in SCN1A subunit of voltage-gated sodium channel; spectrum of disease  —  ranges from susceptibility to febrile seizures at far benign end (caused by polymor­phism in SCN1A) to Dravet syndrome at severe end

Epileptic encephalopathy: age-dependent expression of epilepsy, with onset in childhood but continuing through adulthood; usually results in mental retardation, eg, West (infantile spasms), Lennox-Gastaut (slightly older age of onset), electrical status epilepticus during sleep, and Landau-Kleffner (epileptic aphasia) syndromes; all show strik­ingly abnormal electroencephalography (EEG) and bad cognitive and developmental outcomes

Prognosis: depends on etiology, eg, in patients with tuberous sclerosis and severe Lennox-Gastaut syndrome or in­fantile spasms, outcome probably associated more with tuberous sclerosis; contribution of seizures to outcomes un­clear

Clinical presentations: most children present with febrile seizures, often prolonged or focal 

First case example: 6-mo-old child with prolonged febrile seizure and right hemibody febrile status; patient had normal development, EEG, and brain magnetic resonance imaging (MRI), and negative family history for epi­lepsy, seizures, or febrile seizures; patient treated with diazepam rectal gel (Diastat), and condition diagnosed as prolonged, focal, complex febrile seizure; second episode of febrile status (left hemibody) occurred at 10 mo of age; patient presented with ataxia at 14 mo of age with numerous small seizures (spike-wave stupor), head drops, tripping, and drop spells with no fever; video monitoring showed very frequent poly-spike, slow-wave, and spike-wave discharges, many associated with small myoclonic jerks, drops, or loss of postural control; at 14 mo, development stagnated and began to regress (eg, patient lost ability to speak or understand language); genetic test revealed genotype predictive of severe myoclonic epilepsy of infancy; patient had concomitantly received bursts of steroids for asthma, which reduced frequency of seizures (such seizures previously shown to respond to treat­ment with steroids)

Second case example: 2-yr-old child with history of recurrent prolonged febrile seizures, generalized tonic-clonic seizure, and developmental regression; patient had normal results from previous 2 EEGs and negative family his­tory; video-EEG showed numerous spike-wave discharges associated with minimal head drops; Dravet patients usually refractory to medical treatment

Typical features: include febrile seizures (often prolonged), normal development and EEG during first year, often as­sociated with family history of febrile seizures; during second year, afebrile seizures appear, EEG patterns show generalized spike-wave and polyspike-wave discharges, and developmental stagnation or regression begins; types of seizures  —  vary greatly and include myoclonic, absence (lasting several minutes), and generalized tonic-clonic; stimulus-provoked reflex seizures typical, most commonly (³25%) caused by light; seizures also provoked by hy­perthermia or anxiousness; patients may have recurrent episodes of spike-wave status, nocturnal seizures, and high risk for sudden unexpected death in epilepsy (SUDEP); Dravet has »20% rate of mortality (eg, from status, SUDEP, accident, or trauma) by 20 yr of age; developmental regression and epileptic encephalopathy  —  typical manifesta­tions

Molecular mechanism: SCN1A sodium channel (also called Nav1.1) contains multiple subunits making pore; 70% to 80% of patients in Dravet group have mutations detected by commercial test; additional 15% carry deletions, duplications, or mutations not detected by test; »95% of cases of Dravet syndrome represent de novo mutations, and »5% found in families with GEFS+ (show autosomal recessive pattern of inheritance)

Types of mutations: include variations in copy number, deletions, duplications, and mosaics; different types pro­duce identical clinical features and outcomes; location of mutation may influence outcome; mutation results in loss of function in 60%, always seen in Dravet, and always pathologic; deletions generally associated with severe phenotype; most cases of GEFS+ associated with missense mutations and less disruption of protein structure, but protein does not function correctly; familial hemiplegic migraine also associated with polymorphisms in gene; clinical term severe myoclonic epilepsy borderline assigned to children with clinical phenotype but persistently normal EEG, or abnormal EEG but only febrile seizures (»70% have mutation in SCN1A); basis of disorder prob­ably polygenic (may include key susceptibility factor and another mutation); channel contains element that senses voltage and elements that form pore with narrow waist; mutations in various locations alter function dif­ferently and produce different severities of phenotype; most epilepsies not associated with mutations in SCN1A 

Mouse model: showed knockout of both copies of SCN1A lethal; knockout of single copy results in phenotype like Dravet syndrome (haploinsufficiency); SCN1A expressed very little in human newborns but peaks at 9 to 10 mo of age; afflicted mice develop seizures and ataxia at postnatal day »21 (P21); mice show overall hyperexcitability in brain because g-aminobutyric acid-ergic (GABA-ergic) interneurons, which express sodium channel, do not func­tion; SCN1A expressed differently over time in animals (as in humans); properties of ion channel altered in mice with mutations; during repetitive firing in knockout mouse, progressive decline followed by inability to fire seen in GABA-ergic interneurons; Purkinje cells of cerebellum (inhibitory GABA-ergic interneurons) express SCN1A strongly; consistent with ataxia and crouched gait seen in »59% of children aged 10 to 11 yr with Dravet; with sus­tained firing, dropout seen in knock-out mouse and hyperpolarizing current in hybrid mice; susceptibility to hyper­thermia and seizures  —  study found that wild-type mice could withstand temperatures of »42 C without developing seizures; knockout mice at P18 did not have seizures, but by P20 they developed seizures at 40°; age dependence  —  expression of GABA-ergic neurons shown to change in first weeks in mice and first months in humans

Treatment: stiripentol; new agent with orphan-drug status (indicated only for Dravet syndrome); ketogenic diet somewhat useful; some standard antiepileptic drugs (AEDs) partially effective, but lamotrigine, felbamate, and car­bamazepine exacerbate condition; children who do worse taking valproate may have mutation in mitochondrial polymerase g (POLG1) gene; POLG1 also possibly associated with risk for SUDEP; trials  —  single randomized controlled study added stiripentol to standard regimen of valproate and clobazam (benzodiazepine nearing ap­proval), which resulted in »60% reduction of generalized tonic-clonic seizures

Epileptic encephalopathy: oscillations may represent common link between seizures and epileptic encephalopathy; study in rats showed hippocampal place cells (responsible for orientation) fire rapidly and replay firing during sleep; if process interrupted by seizure or spike, rats fail to remember orientation; oscillatory behavior in brain may play important role in process; children with Dravet have poor memory; recent study  —  found no abnormalities in spectra of EEG among children with Dravet <2 yr of age; at 3 to 5 yr of age, significant decreases in percentage of a-rhythms and slowing of EEG observed (medication may play role); at >6 yr of age, marked increase in q-and clear decrease in a-rhythms observed; changes in EEG reflected changes in development; mutations may result in age-related changes in oscillatory processes; in rodents, q-oscillations critical for regulation of learning and state; g-oscillations important for memory in humans; unknown whether changes in coordination of networked activities contribute more to cognitive outcomes than seizures; relationship between oscillations and autism also under inves­tigation

Mechanisms of Acupuncture

Helene Langevin, MD, Professor of Neurology, Orthopedics, and Rehabilitation; Director, Program in Integra­tive Health, University of Vermont, Burlington

Acute conditions: conditions for which data support clear benefit include nausea related to surgery and chemother­apy and postoperative pain; repetitive stimulus applied for these conditions, eg, rubbing wrist over median nerve or applying pulses of electrical stimulation at »2 to 10 Hz

Chronic conditions: most patients seek acupuncture for chronic pain; large-scale trials  —  performed for chronic conditions, eg, low back pain, migraine and tension headaches, and osteoarthritis of knee; mode of stimulation dif­fered from repetitive type used for acute conditions, ie, needles inserted, rapidly manipulated, left in place for »30 min, and removed; types of sham controls used included shallow insertion of needle without manipulation, inser­tion in wrong place, or use of pressure without insertion; critical that patient cannot distinguish therapy from sham to control for placebo effect; results  —  in all trials, acupuncture and sham performed equally, with both better than standard care; evaluation of performance in clinical practice showed acupuncture superior to standard care; data suggest therapeutic benefits result from nonspecific placebo effects

Nonspecific placebo effects: more elaborate or impressive procedures produce stronger placebo effects; effects ap­parent in drug trials also; components that contribute to healing include expectancy, conditioning (positive experi­ence from treatment facilitates better response from future treatments), self-healing, context, and motivation

Nonspecific components of acupuncture: additional time involved in therapy; reframing of problem; palpation along meridians; education of patients and lifestyle interventions

Effects of needles: study used ultrasonography (US) to measure displacement of connective tissue (perimuscular fas­cia) during insertion and manipulation of needles up to 5 mm; found indentation of skin with toothpick (no penetra­tion) up to 5 mm caused more movement of perimuscular fascia than penetration with needle; shams that do not puncture skin may still affect tissues

Neuroimaging: study used functional MRI and positron emission tomography (PET) to measure potential to bind opioids in specific areas of brain of patients with fibromyalgia; relief of pain equal in patients who received acu­puncture or sham, but effects in brains differed significantly; patients in different groups possibly benefited for dif­ferent reasons

Animal experiments: hypothesis  —  manipulation of needles causes release of adenosine, which binds adenosine A1 receptor locally on sensory afferents; results  —  in knockout mice that lacked A1 receptor, effects of acupuncture abolished; relationship between physiologic response in animals and therapeutic response in humans unknown

Effects on connective tissue: during acupuncture, important to rotate or manipulate needle until patient feels deep sensation and clinician feels something “grabbing” needle; manipulation of needle shown to increase force required to withdraw needle; studies in rats showed subcutaneous collagen winds around needle during manipulation caus­ing grabbing; insertion and rotation of needle in tissue ex vivo caused 20% stretching of processes of fibroblasts and 200% increase in cross-sectional area of cells; maximal cross-sectional area achieved at 2 turns of needle, and re­sponse diminished with increasing number of turns thereafter; bidirectional rotation by 180°, 360°, and 720° for different numbers of cycles produced similar nonmonotonic dose effect; response took longer with bidirectional ro­tation; effect measurable at distance of £3 cm from needle in mice

Meridians: specific lines in which needles placed; US revealed funnel-like structures at acupuncture sites, represent­ing planes of connective tissue separating muscles; optimal access to connective tissue may explain heightened re­sponsiveness at meridians; study in cadaver found 80% of acupuncture points located near 1 to 3 fascial planes; meridian networks  —  theoretically meridians interconnect all parts of body, as does connective tissue; network of connective tissue may explain distant effects of acupuncture; injuries  —  scar tissue can thicken and fuse fascial lay­ers; may cause pain (eg, chronic low back pain); study found 25% increase in echogenicity and thickness of thora­columbar fascia in patients with chronic low back pain; during movement, less shear strain between fascial layers observed in patients with low back pain, and layers moved more in unison; unknown whether phenomenon results from muscle or connective tissue pathology

Recommendation to patients: arguments against  —  effects not different from those of sham; arguments in favor  —treatment safe and beneficial compared to standard care; data has shown cost effectiveness; caveat  —  mechanism not currently understood

Future avenues of research: nature of placebo response; therapeutic mechanisms of acupuncture, eg, whether acu­puncture boosts healing response, patient benefits by learning something from treatment, or treatment has specific physiological effects

Acknowledgements

Drs. Morse and Langevin spoke at the Northern New England Neurological Society Annual Meeting 2011, held Oct 21-22, 2011, in Portland, ME, and presented by the University of Vermont College of Medicine in alliance with Fletcher Allen Health Care (to learn more about other CME meetings presented by the University of Vermont College of Medicine in Alliance with Fletcher Allen Health Care, visit www. cme.uvm.edu). The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the pro­duction of this program.

Suggested Reading

Ahn AC et al: Electrical impedance of acupuncture meridians: the relevance of subcutaneous collagenous bands. PLoS One 5:e11907, 2010; Castro-Gago M et al: Dravet syndrome and mitochondrial dysfunction. J Child Neurol 26:1331, 2011; Ceulemans B: Overall management of patients with Dravet syndrome. Dev Med Child Neurol 53 Suppl 2:19, 2011; Chiron C: Current therapeu­tic procedures in Dravet syndrome. Dev Med Child Neurol 53 Suppl 2:16, 2011; Craig AK et al: Dravet syndrome: patients with co-morbid SCN1A mutations and mitochondrial electron transport chain defects. Seizure Sep 7, 2011 [Epub ahead of print]; De Jonghe P: Molecular genetics of Dravet syndrome. Dev Med Child Neurol 53 Suppl 2:7, 2011; Finando S, Finando D: Fascia and the mech­anism of acupuncture. J Bodyw Mov Ther 15:168, 2011; Fountain-Capal JK et al: When should clinicians order genetic testing for Dravet syndrome? Pediatr Neurol 45:319, 2011; Guerrini R, Falchi M: Dravet syndrome and SCN1A gene mutation related-epilep­sies: cognitive impairment and its determinants. Dev Med Child Neurol 53 Suppl 2:11, 2011; Hopton AK, Macpherson H: Assess­ing blinding in randomized controlled trials of acupuncture: challenges and recommendations. Chin J Integr Med 17:173, 2011; Julias M et al: Varying assay geometry to emulate connective tissue planes in an in vitro model of acupuncture needling. Anat Rec (Hoboken) 294:243, 2011; Molsberger A et al: An international expert survey on acupuncture in randomized controlled trials for low back pain and a validation of the low back pain acupuncture score. Eur J Med Res 16:133, 2011; Mulligan JE, Mandelbaum DE: Myoclonic astatic epilepsy and the role of the ketogenic diet. Med Health R I 94:127, 2011; Petrelli C et al: Early clinical features in Dravet syndrome patients with and without SCN1a mutations. Epilepsy Res Nov 7, 2011 [Epub ahead of print]; Specchio N et al: Electroencephalographic features in Dravet syndrome: five-year follow-up study in 22 patients. J Child Neurol Oct 21, 2011 [Epub ahead of print]; Terry R et al: An overview of systematic reviews of complementary and alternative medicine for fibromyalgia. Clin Rheumatol May 26, 2011 [Epub ahead of print]; Wang SJ, Young WB: Needling the pain and comforting the brain: acupuncture in treatment of chronic migraine. Cephalalgia Oct 12, 2011 [Epub ahead of print]; Witt CM: Patient characteristics and variation in treatment outcomes: which patients benefit most from acupuncture for chronic pain? Clin J Pain 27:550, 2011; Yamakawa K: Mo­lecular and cellular basis: insights from experimental models of Dravet syndrome. Epilepsia 52 Suppl 2:70, 2011.