Monday, April 30, 2007

Swallowing rehab measures in dysphagia due to inflammatory myopathy

Diet -- oral, nonoral (PEG) or both
Feeding instructions-- chew food well, swallow twice, small bites, alternate solids and liquids, sit upright during the meal.
Compensation-- Chin tuck, head turn (right and left) , effootful swallow, Mendelsohn maneuver, supraglottic swallow
Exercises-- tongue base retraction, effortful swallow, Mendelsohn maneuver, falsetto, supraglottice swallow.
Interventions done-- cricopharyngeal myotomies most helpful and were most frequently done in IBM  Other procedures done were cricopharyngeal or esophageal dilatation, and PEG. 

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Malignant transformation of monoclonal gammopathy

Rosinol L. et al.  Mayo Clin Proc 2007;82:428-434.
The authors cite a NEJM article (2006) showing a prevalence of 3.2 % and 5.7 % in patients greater than 50 and 70, respectively.  The patients can transform after years of stability.  To determine the rate of transformation, the authors took into account both the presenting clinical finding and the evolutionary pattern of the M protein.  They excluded patients diagnosed in the first 3 years, or with smoldering myeloma.  537 were diagnosed with MGUS, 178 were lost to followup or were followed les than three years, 359 were followed more than 3 years.  Patients received a SPEP, UPEP and bonemarrow aspirate.  On followup they got an M protein measurement on pep yearly. Evolving type was defined as patients with an increase in the M protein size on electropheresis in each annual visit over three years.  330 patients were nonevolving and 29 were evolving.  32 developed malignancies.  Risk factors were the evolving typeand M protein concentration.  Of the 32 malignancies, 20 had multiple myeloma and 2 had Waldenstrom's macroglobulinemia after a median followup of 93 months (7 and a half years, just under ten percent).  However, 14/29 with evolving MGUS (48 %) developed symptomatic disease, and 18 (5%) on nonevolving progressed.  The rate of transformation in the evolving and nonevolving groups after ten and twenty years, respectively, were, 55 and 10, and 80 and 13, respectively. 
Initial factors associated with transformation were M protein size greaterthn 15 g/L, proportion of BMPCs (bonemarrow plasma cells) greater than 5 %; higher incidence of IgA v. IgG, and evolving MGUS. No nonevolving patients transformed after twelve years. 
The actuarial rate of progression is 1.5 % per year, 17 % at 10 years, 34 % at 20 years, 39 % at 25 years (Kyle et al., different paper).  Baldini et al. (Blood, 1996) emphasizes BMPC's as an important risk factor with followup of patients with BMPC ranging from 10-30 percent (normal was around 4) having a 5-6 year followup, having a rate of malignant transformation of 37 v. 7 percent.  Cesana et al.  (J Clin Oncol 2002) found bm plasmacytosis greater than 5 percent, presence of light chains proteinuria, polyclonal serum immunoglobulin reduction and high ESR as independent factors affecting transformation.  Kyle et al. found thatM protein size and non IgG type were the most important predictors of progression.  (Kappa v. lambda had relative risk of 4.1).  Rajkumar et al.(Blood 2005)found non IgG MGUS, M protein > 15 g/L, abnormal k/l light chain ratio had an actuarial probability of transforming of 58 % at 20 years, whereas patients who lacked all of the above risk factors had a rate of transformation at 20 years of only 6 percent. 
Kyle and Greipp(NEJM 1980) described SMM (smouldering multiple myeloma), defined as M protein > 30 and BMPC> 10 % without end organ impairment.  Patients with the evolving SMM type show a progressive increase in M protein until myeloma develops,  whereas nonevolving types have stable M protein until the onset of disease with a longer time till disease develops.  59 % of SMM patients who were evolving previously had an evolving MGUS, whereas only 4 % of nonevolving SMM had a previously noted MGUS .  This is due to genomic hybridization, with high chromosomal losses and iq gains in the evolving patients.
The authors hypothesize that there are two types oo MGUS evolving and nonevolving, and all patients with the evolving type will eventially get disease. 

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Sunday, April 22, 2007

Internuclear opthalmoplegia: Unusual causes in 114/410

Keane JR. Arch Neurol. 2005; 62:714-717. Uunusual causes not stroke or MS occur in 28 % overall, 42 % of unilateral cases the author has seen over three plus decades in practice. Of 410 cases, 38 % (157)were due to stroke (5.157 due to cardiac emboli), 139 (34 %) due to MS, and 114 (28%) due to "unusual" causes. These included 16 patients with blunt head injury, one gunshot wound, and one with blood loss after a stabbing. Two motor vehicular collisions led to vertebral artery injury after cervical spine fracture. Tentorial herniation after CNS infection occurred in 2; one had a subdural empyema , bilateral SDH, TB meningitis There were two cases of brainstem toxoplasmosis, 1 lymphoma and 3 brainstem encephalitis, all inHIV patients. 4 patients with cysticercosis had lesions in caudal aqueduct or fourth ventricle. Two patients had neurosyphilis. 12 patients had iatrogenic injury including angiography, tumor emobolization, CEA, cardiac catheterization, 1 hydrocephalus, 1 Wernicke's encephalopathy, 1 brainstem atrophy, one carbamazepine overdose, one cerebellar hemorrhagic infarct with pontine compression, one spinocerebellar atrophy with pigmentary changes.

Pseudo INO was seen in 27/182 patients with myasthenia gravis, 2 patients with GBS, 1/38 with Fisher s, 1 with abetalipoporoteninemia, andcalorics showed an INO pattern in several comatose patients. PSP shows preferential weakness of the medial rectus with improvement with caloric stimulation.

Delirium due to consuming toner cartridge cleaner

Tancredi DN , Shannon MW. Case 30-2003: A 21 year old man with sudden alteration of mental status. The patient was a 21 year old who b had been drinking, then acted strangely, smelled of urine, awake and noncommunicative. Pupils were reactive. Iv droperidol resulted in coma, then hyperagitation. He had consumed laser printer toner cartridge cleaner to augment the effects of alcohol, that is metabolized to GABA. He awoke and insisted on leaving.
Discussion comments on gamma hydroxybutyrate that was used in the 1980s by bodybuilders, enhanced ethanol,date rape drug, but is still manufactured illegally, quite easily, at home. Criminalization led to the use of congeners. Gamma butyrolactone has since been restricted. Gamma valerolactone is a solvent in industrial applications. This patient took 1,4 butanediol which is used in compact disc and printer cleaners, but is legal. It metabolizes to gamma hydroxybutyrate which acts at specific receptors and at the GABA b receptor. Intoxication shows about one third have hypothermia, bradycardia, or both, are inebriated with an agitated delirium. Severe effects are coma and apnea, which uniquely, resolves extremely rapidly with a return to awareness. Amnesia occurs. Ethanol inhibits alcohol dehydrogenase, halting the metabolism of 1,4 butanediol. There may be a biphasic period of risk of coma due to interactions and patients should have prolonged observation. Treatment is supportive. Studies are underway using 4-methylpyrazole (fomepazole) an alcohol dehydrogenase inhibitor also being studied in methanol and ethylene glycol intoxication. More clinical information can be found here:

See discussion of SSADH here:

Cavernous carotid aneurysms

One third are asymptomatic at diagnosis, one third have headaches, and one third have cranial neuropathy (3,4,5,6). HA may resolve with gabapentin. Associations of include htn, multiple aneurysms, connective tisue diseases such as Ehler-Danlos s. type 4 and xanthoma elasticum.

Differential of trigeminal headaches &blink reflex

SUNCT (see separate entry)
cervical (c2) myelitis with occipital headache
cavernous sinus syndrome-- aneurysms
pituitary tumor
cavernous sinus malignancy

Evaluation of:
Blink reflexes were abnormal in 15 % of patients with atypical facial pain . 35 % of patients showed decreased habituation of the blink reflex. Thermal QST was abnormal in 55 % with abnormal facial pain and in all with trigeminal neuropathy. Blinks could help sort out brainstem and peripheral lesions, the trigeminal neuropathy patients. Source Forssell H et al. Neurology 2007; 69:1451-9. (authors are Finnish, and so am I)

Smallpox and bioterrorism and the neurologist

Variola infection requires only a few drops inhaled from oral, nasal or pharyngeal mucosa. Infected patients may shed virions one or two days before symptoms until all scabs and crusts are shed. They are most infectious in first ten days. It produces an asymptomatic viremia, followed by a toxic viremia when it spreads to the spleen and other organs.

Neurologic symptoms include splitting headaches with pain over whole or just lumbar spine, hallucinations, delirium, depressive psychosis, manic depressive states that all may last into convalescence. Ocular disease (variola residua) may be bilateral with loss of sight from leukoma adherens or complications causing enucleation .

Intravenous cidofavir which is nephrotoxic may be useful. Smallpox vaccine (vaccinia virus) within seven days after exposure (incubation period) can prevent or attenuate the disease. Contraindications to preexposure vaccination are immunosuppression, HIV infection, pregnancy, or household sexual contacts with contraindications. Such patients should get vaccinia immune globulin with smallpox vaccine, but it may be unavailable.

Postvaccinial encephalitis is seen almost exclusively in those getting primary vaccination. In kids younger than 2 it can occur in 6-10 days,with most patients dying. In those older than 2, it has 35 % mortality, or those who recover do so within two weeks. Strain used may be important. Authors favor preexposure vaccination and stockpiling of vaccinia immune globulin. Eczema vaccinatum results from vaccinating an atopic patient or contacts of someone with eczema.

Pitfalls-- confusing generalized vaccinia, vaccinia necrosum or eczema vaccinatum with true smallpox, therefore rapid development of a pcr test is needed. Another pitfall is vaccinating an immunocompromised individual, that may have a 33 % mortality.

Neurologic symptoms of anthrax

The major one is fulminant and rapidly fatal hemorrhagic meningoencephalitis. Fever with neurologic deterioration and dark necrotic pustules on the extremities, gram postive rods in CSF and multifocal cerebral bleeding, anthrax should be considered. Inhalational form is muchmore likely to cause the above than cutaneous forms. Death usually occurs within one week. Conversely, headache and confusion are common presenting signs.

Posterior thalamic hemorrhage and pusher syndrome

Karnath HO et al Posterior thalamic hemorrhage induces "pusher syndrome." Neurology 2005; 64: 1014-1019.
The syndrome occurs when stroke patients use an unaffected limb to "push" away from nonparalyzed side. Authors have found subjects with posterior thalamic stroke experience their body as upright when it is actually are tilted 20 degrees towards the lesional side. The result of the contraversive pushing is loss of postural balance and falling. The study involved about 46 thalamic stroke patients.

Forearm exercise screening test for mitochondria myopathy

Jensen TD et al. A forearm exercise screening test for mitochondrial myopathy. Neurology 2002; 58:1533-1538. Authors comapred 12 patients with MM to 10 with mucular dystrophy and 12 normal controls. All subjects performed intermittent handgrip exercise (squeeze one second, rest one second) for 3 minutes. Blood samples were collected from median cubital vein before during and after exercise to measure oxygen saturation and lactate levels. MM patients did not have the normal oxygen desaturation seen in other subjects. The lactate test did not show a significant change. The authors propose this as a sensitive and specific screening test for MM, almoot as good as muscle biopsy.

Localization of orgasmic seizures (aura)

Janszky J et al. Orgasmic aura originates from the right hemisphere Neurology 2002; 58:302-304. The authors reviewed 2 new cases and 22 already published. Among 15 with unilateral eeg foci, 13 (87%) had right and 2 (13%) had left hemisphere focus. The lesions included right temporal AVM, 3 had right postcentral parasaggittal focus. Authors comment on the rarity of auras have lateralizing value and this being an exception among epilepsies. Reviewing the chart, several patients had left hand or leg jerking, ictal speech, sitting, automatism, a sensation of fear. Authors believe amygdala is important, but that parasaggittal cases are due to stimulation of the cortical areas important for genital sensation.

Localizing value of the abdominal aura

and its evolution. A study in focal epilepsies. Henkel et al. Neurology 2002; 58:271-276. Abdominal auras were more common in TLE than in extratemporal epilepsy. (52 % v 12 %). They also were more frequent in mesial TLE and than cortical TLE. Abdominal auras were followed by oral and manual automatisms in 100 % of patients with TLE and only 2/13 patients with extratemporal epilepsy. The evolution of an abdominal aura into an automotor seizure increases the likelihood (probability) of TLE to 98.3 %.

Immune reconstitution s. ass c PML/AIDS

MArtinez JV et al. Neurology 2006; 67:1692-1694. A patient with PML due to HIV received HAART and deteriorated. He developed enhancing lesions. HAART wa stopped for 2 weeks, and he was given dexamethasone 32 mg/day with slow taper, and partially imnproved.

Paraneoplastic syndromes involving the nervous system

Darnell R B and Posner JB. NEJM2003; 349:1543-54. Review article . Mechanisms of disease.

Authors discuss immune mediated diseases, affecting 0.01 percent of patients with cancer. However some are more common. LEMS affects 3 % of patients with small cell lung cancer, and mg affects 15 % of patients with thymoma, and demyelinating neuropathy affects 50 % of patients with sclerotic form of multiple myeloma (rare form).

Neurologic condition usually appears first, and cancer searches may be unrewarding, and whole body PET scan should be considered. CSF pleocytosis may dissipate but elevated IgG may persist. The predominant cell type is T cells.

Clinical conditions include
Limbic encephalitis
brain stem encephalitis
cerebrellar degeneration
visual syndromes ((cancer associated retinopathy and ON)
necrotizing myelopathy
inflammatory myelitis
motor neuron disease
subacute motor neuropathy
stiff person syndrome
sensory neuronopathy
autonomic neuropathy
acute sensorimotor neuropathy
polyradiculpathy (GBS)
brachial neuritis
chronic sensorimotor neuropathy
vasculitic neuropathy
myasthenia gravis
necrotizing myopathy

Antigens that are present do not cause neurologic disease unless they cross the blood brain barrier and react with neurons expressing the onconeural antigen.

patients with Hu antigens mayhave small cell lung cancer restricted to a nodule despite that most small cell lung cancers are metastatic at diagnosis. The prognosis of the cancer may also be better, even, eg. among patients with anti Hu antibodies who lack a paraneoplastic syndrome. T cells are critical elements of the response. They may be activated by apoptotic tumor cells. In a few conditions, antibody responses are more important, including LEMS, MG and a rare form of cerebellar degeneration. These forms have antigens that are cell surface receptors. Anti Sox antibodies are thought predictive of SCCL in LEMS

Immune treatments are widely used but not known to be effective. Keine-Guibert protocols IVIG .5 g/kg for five days, iv methylprednisolone at 1 g/d for 3 days and iv cyclophosphamide at 600 mg/m(2) of body surface area for one day on day 4. The treatment can be repeated if it appears effective, at 3 week intervals, or if prednisolone was effective, using one day per month of ivig/steroid/cytoxan together. Also used is tacrolimus, .15 mg/kg/d for 14 days, then .3 mg/kg for 7 days.

Saturday, April 21, 2007

SUNCT syndrome and SUNA syndrome & PH

These are grouped as trigeminal autonomic cephalgias, together with cluster headache. (TACs)

SUNCT= short acting unilateral neuralgiform headache with conjunctival injection and tearing. Usually SUNCT headaches are retroorbital with stabs, groups of stabs or sawtooth pain and may occur 3-200 times per day and last 15-240 seconds. They are strictly unilateral and may resemble paroxysmal hemicrania, cluster headache or trigeminal neuralgia. They may resist treatment although in one case in Neurology a patient responded to topiramate, AAN2009 lamictal was reported as drug of choice. Men experience it more in a 2:1 ratio, whereas paroxysmal hemicrania occurs more in women and last 15 minutes v. less than a minute for SUNCT. The location of the pain is supraorbital, orbital, retroorbital, temporal, in the top or side of the head, in a V2 or V3 distribution, or in the teeth, neck or ear. All patients have conjunctival injection and tearing. GBN also has been used. Neurology(2002) patients with pituitary tumors (adenomas) after beginning therapy with bromocriptene. Other cases are triggered by exercise. In the above series, authors speculate that extension of the tumor into the cavernous sinus may be contributory.

In Cohen AS et al, Brain 2006 (129:2746-2760) a series of 43 patients were reported with SUNCT and 9 with the less known SUNA syndrome. 2 SUNA patients had tearing, 4 had conjunctival injection but none had both. Other cranial autonomic features seen include nasal blockage, rhinorrhea, eyelid edema, facial sweating, flushing or ear flushing. Most patients did not have a refractory period between attacks and were agitated with the attacks. Pain severity is greater in SUNCT than SUNA. In general analgesic overuse ought to be avoided.

SUNA stands for "Short-lasting Unilateral Neuralgiform headache Attacks with cranial autonomic symptoms." Occassionally it can present with Horner's syndrome.

Other pearls for diagnosis: ipsilateral photophobia and phonophobia differentiates TACS from migraines. Interictal pain occurs in one third, often those with personal/family history of migraine. In patients with cluster headache, more than half have OSA so do a sleep study. TAC like pain occurs at a very high rate with pituitary tumors, so MRI with pituitary thin cuts is indicated.

Paroxysmal hemicrania (PH) has a unilateral brief headache attack that occurs several times daily. It most often but not exclusively affects first division of trigeminal nerve. It lasts 2-30 minutes (longer than SUNCT/SUNA) with 1-40 attacks per day, and may be episodic in 20 percent (attacks for up to a week with a month or more remission between) or chronic in 8- percent with no remission of remission of less than a month. Distinctively, it responds to indomethacin.

(I try to AVOID basic science but) common to all 3 is activation of posterior hypothalamus on all syndromes.

Symptomatic (or secondary) TACs occur rarely, and clinical features alerting to possibility include atypical phenotype, abnormal exam, and refractory to treatment. Summarized by Cittadini et al (Neurologist 2009; 15: 305-312) include historical points such as unusual triggers such as postprandial, or sitting or standing; altered consciousness, impotence, galactorrhea, acromegaly, fever, and purulent nasal discharge. Physical signs included opthalmoplegia, optic atrophy, temporal hemianopia, Adie syndrome, swelling of the eye, persistent partial or complete Horner's syndrome, absent nasal tickle reflex, signs of acromegaly, testicular atrophy, and absent radial pulse. In PH atypical features included onset with carotid massage (gangliocytoma extending to carotid artery from pituitary lesion).

Since one in ten patients may have incidental pituitary microadenoma and one in 500 an incidental macroadenoma, the role of imaging may be less certain, with decided risk of unknown importance of discovering and treating an incidental finding.

AAN 2010 suggested SUNCT/SUNA responsive to occipital stimulator

Applause sign is specific clinical test for PSP

Dubois B et al. "Applause sign" helps to discriminate PSP from FTRD and PD. Neurology 2005;64: 2132-2133. When asked to clap three and only three times as quickly as possible, after demonstration by examiner, an inability to stop clapping indicates PSP. Clapping from 4->10 times is abnormal. An applause sign was seen in 71 % of patients with PSP but none with FTD or PD.

a separate article described superior cerebellar atrophy in PSP

Drop attacks due to superior canal dehiscence

Brantberg K, Ishiyama A, Baloh RW. Drop attacks secondary to superior canal dehiscence syndrome. Authors describe 2 patients. They note drop attacks occur in late Meniere's syndrome but can be early as well with vestibular dysfunction and normal hearing. They are in these cases associated with a sensation of being pushed or environmental tilts.

SCD is a peripheral audivestibular disorder manifested by sound and pressure induced vertigo due to absent bone coverage at the apex of the semicircular canal. The diagnosis is by inducing vertical or torsional eye movements in the plane of the superior canal when exposed to sounds or pressure changes. High resolution CT shows bony dehiscence in canal. Audiological tests show increased threshold in the low frequency range for air but not bone conduction.

The 2 patients described with unprovoked drop attacks not provoked by coughing, straining or loud noises (Tullio phenomenon).

Malignant transformation in MGUS

Eurelings M et al. Maligannt transformation in polyneuropathy associated with monoclonal gammopathy. Neurology 2005; 64:2079-2084.
Of 193 patients with MGUS and polyneuropathy, 17 had a hematologic diagnosis at onset. The rate of transformation in the remaining patients was 2.7 % per year. Independent predicting factors associated with transformation were progressive neuropathy, weight loss, fevers, night sweats and Mm-protein level.
Notes: diagnotic criteria for MGUS include M proteinlevel< 30 g/dl, bm plasma cell infiltrate of less than 10 %, absent lytic lesions in bone, anemia, hypercalcemia, renal insufficiency, and stable M protein level, as well as absent fatigue, weight loss, bone pain or susceptibility to infections. There was no effect of IgG v IgA or kappa v lambda

Intermittent third nerve palsy ddx

Cluster HA
cryptococcus n. infection meningitis
cavernous sinus lesion
pituitary lesion

Laryngospasm in Kennedy Syndrome

Sperfeld AD et al. Laryngospasm. An underdiagnosed symptom of x-linked spinobulbar muscular atrophy. Neurology 2005;64: 753-4. L is defined as the sudden onset of the sensation of the inability to move air in and out, lasting a few seconds and followed by stridor. It occurred in 23/49 patients surveyed with KS. Itsalso associated with GERD.

Paparounas K. Kennedy disease: insights and conclusions. Arch neurol (correspondence) 2004;61: 603. Distinctive features that are virtually pathognomic of the disease include (in the originally cited article) endocrine features such as gynecomastia. The author states that perioral fasciculations and facial fasciclations are present in 95 % of patients and are "highly characteristic if not pathognomonic." Its not found in any other disease. KD patients also have decreased vibratory sense, especially in the feet, even among patients without sensory dysfunction. The original author responded that perioral fasciculations are a late finding.

The diagnosis of Kennedy syndrome or SBMA (spinal bulbar muscular atrophy) by a simple blood test (Athena) is important because SBMA has a much more benign course with a 10 year survival of 82 % with no PEG use and only rare CPAP use. (Chahin et al. Neurology 2008:70:1967-1971.

Segawa disease DYT 5

AD guanosine triphosphate cyclohydrolase I (GTP-1_ deficiency. Thsi is a hereditary doap response generalized dystonia, typically with onset in childhood, that responds to low dose levodopa. It is due to partial deficiency of tetrahydrobiopterin.

Clinical pearls include the presentation with equinovarus by age 6, and four extremity dystonia by teens, difficulty with hand pronation/supination, marked diurnal fluctuation, and rarer findings such as writer's cramp or guitarist's cramp. Adult onset may have bradykinesia,, tremor mimicking PD, or focal hand dystonia.

Rheumatoid pachymeningitis

Starosta MA et al. Clinical manifestations and treatment of r.p. Neurology 2007;68:1079-1080.

Disorder can occur early or after many years of RA, RF and ESR are usually elevated but the esr may be only middling. The usual presentation is headache or cn palsy esp cn 8. On biopsy, unlike autopsy, nodules are infrequently found, in dura, and path showsx inflammatory cells, fibrosis. In autopsy series, the finding is nodules with central necrosis with histiocytes and mononuclear esp. plasma cells. Treatment with prednisone and other drugs (MTX, cytoxan) are effective.

Rash to yellow dye in levodopa-carbidopa

Chou KL , Stacy MA. Skin rash associated with simemet does not equal levodopa allergy. Neurology 2007; 68: 1078-9. Patients experiencing a rash on sinemet requiring stopping and rechallenging were actually allergic to a yellow dye (D&C Yellow 10 and FD&C Yellow 6) and were able to tolerate forms of levodopa not containing the dye. The safe forms included C/L 25/250 or 10/100 , CR forms of Sinemet, Stalevo and Parcopa, or Madopar (benserazide/levodopa).