Crino et al. NEJM 355:13: 1345-1356 The Tuberous Sclerosis Complex [Review article}
TSC is a multisystem autosomal dominant disorder affecting children and adults, resulting from mutations in one of two genes, TSC1(encoding hamartin) or TSC2 (encoding tuberin).
Neurologic disorders include epilepsy, mental retardation, and autism. Other features are facial angiofibromas (formerly adenoma sebaceum), renal angiomyolipomas, and pulmonary lymphangiomyomatosis. TSC has a wide spectrun of disease ranging from subclinical to severely affected. Clinical trials utilizing tuberin and hamartin are underway.
The diagnosis is made clinically using major and minor criieria. Genetic tests are currently considered corroborative. Diagnosis may be made by developmental stage specific findings.
Renal disease (angiomyolipomas) occur in up to thre fourths, may be vascular, may sometimes be treated with embolization, and are most dangerous if greater than 3 cm in size.
Wednesday, September 27, 2006
transfusion related infections
Blajchman MA and Vamvakas EC. The Contining risk of transfusion-transmitted infections. NEJM 355:13: 1303-1305 Sept 28 2006
Authors remind us of risks to the blood supply. Neurologically speaking, culprits include West Nile Virus which is now mandated to be screened. vCJD (Variant CJD) with an incubation period oo up to 50 years has probably been transmitted in three cases in Britain. HHV8 a herpesvirus akin to CMV causes lifelong infections with periodic reactivations during which virus can circulate in WBC's and be transmitted. Risk factors probably overlap with HBV HCV and HIV andmayinduce Kaposi's sarcoma. No simple screening assay exists. Transfusing leukocyte reduced PRBC's may reduce transmission but this is unproved.
Discussion in blood bank circles includes whether to use pathogen reduction technologies such as methylene blue or solvent detergent, amotosalen for platelets, and UVA for RBC's.
Authors remind us of risks to the blood supply. Neurologically speaking, culprits include West Nile Virus which is now mandated to be screened. vCJD (Variant CJD) with an incubation period oo up to 50 years has probably been transmitted in three cases in Britain. HHV8 a herpesvirus akin to CMV causes lifelong infections with periodic reactivations during which virus can circulate in WBC's and be transmitted. Risk factors probably overlap with HBV HCV and HIV andmayinduce Kaposi's sarcoma. No simple screening assay exists. Transfusing leukocyte reduced PRBC's may reduce transmission but this is unproved.
Discussion in blood bank circles includes whether to use pathogen reduction technologies such as methylene blue or solvent detergent, amotosalen for platelets, and UVA for RBC's.
Friday, September 22, 2006
Neuropathy treatments
MMN distal> proximal, +GM1, +IVIG, Cytoxan, ppx
MADSAM Lewis Sumner syndrome= MMN with sensory symptoms, distal>proximal +IVIG, + prednisone, ?cytoxan, ? Ppx
DADS -- rituxan role?
MADSAM Lewis Sumner syndrome= MMN with sensory symptoms, distal>proximal +IVIG, + prednisone, ?cytoxan, ? Ppx
DADS -- rituxan role?
Saturday, September 09, 2006
Mestinon for OH
Singer et al. Pyridostigmine treatment trial in neurogenic orthostatic hypothension. Arch Neurol 2006; 63:513-518.
Pyridostigmine may improve OH especially diastolic BP without affecting systolic BP due to effect on efferent limb of baroreflex in a 2 neuron system synapsing at the autonomic ganglion.
Study was a 4 way crossover study at Mayo Clinic in MN on 56 patients. Finding was that alone or with low dose midodrine alleviates OH without exacerbating HTN
Pyridostigmine may improve OH especially diastolic BP without affecting systolic BP due to effect on efferent limb of baroreflex in a 2 neuron system synapsing at the autonomic ganglion.
Study was a 4 way crossover study at Mayo Clinic in MN on 56 patients. Finding was that alone or with low dose midodrine alleviates OH without exacerbating HTN
CTX signs and lack thereof
Verrips et al. Presence of diarrhea and absence of tendon xanthomas in patients with cerebrotendinous xanthomatosis. Arch Neurol 2000; 57:520-524
Summary: study of 27 adults and 5 children at Netherlands. Only 41 % had tendon xanthomas at diagnosis. 97 % had premature cataracts and 81 % had long tract signs, 66 % had low intelligence and 56 % had cerebellar signs. Half had severe intractable diarrhea that started in childhood. Suggests CTX is underdiagnosed and should be sought in patients with cataracts and early diarrhea irrespective of neurologic disease.
Summary: study of 27 adults and 5 children at Netherlands. Only 41 % had tendon xanthomas at diagnosis. 97 % had premature cataracts and 81 % had long tract signs, 66 % had low intelligence and 56 % had cerebellar signs. Half had severe intractable diarrhea that started in childhood. Suggests CTX is underdiagnosed and should be sought in patients with cataracts and early diarrhea irrespective of neurologic disease.
Late onset Fabry's disease
Nance et al. Later onset Fabry disease. An adult variant presenting with cramp-fasciculation syndrome. Arch Neurol 2006; 63:453-457.
Fabry disease is an X linked recessively inherited disease due to deficient/absent lysosomal alpha galactosidase and accumulation of globotriaosylceramide (GL-3) and glycososphingolipids in plasma and cellular lysosomes. Classically, male onset occurs in childhood with episodic painful burning sensations in the hands and feets (acroparesthesias), typical skin lesions (angiokeratomas), hypohydrosis, and corneal opacities. Later, patients develop CRF, cardiac valvular disease and strokes, and die by 50s.
Late onset variants typically have renal or cardiac disease without typical neurologic stigmata in sixth decade or later.
Case report is of 34 year old man with activity induced cramps and fasciculations. Nerve biopsy, and pan MRI were negative. Mother had similar syndrome, with painful walking, and had a stroke at 37. Patient's alpha Gal A was deficient, leading to diagnosis.
Other features
Dolichoectasia of cerebral vessels
TIA
Vertigo
Hearing loss
Tinnitus
Cognitive disorders
Small fiber neuropathy
Painful acroparesthesias
Hypohidrosis
Impaired temperature sensation
Intestinal dysmotility
Cardiomyopathy
Cardiac conduction abnormality
Renal failure
Angiokeratomas
Corneal dystrophy
Feathery opacities
Fabry disease is an X linked recessively inherited disease due to deficient/absent lysosomal alpha galactosidase and accumulation of globotriaosylceramide (GL-3) and glycososphingolipids in plasma and cellular lysosomes. Classically, male onset occurs in childhood with episodic painful burning sensations in the hands and feets (acroparesthesias), typical skin lesions (angiokeratomas), hypohydrosis, and corneal opacities. Later, patients develop CRF, cardiac valvular disease and strokes, and die by 50s.
Late onset variants typically have renal or cardiac disease without typical neurologic stigmata in sixth decade or later.
Case report is of 34 year old man with activity induced cramps and fasciculations. Nerve biopsy, and pan MRI were negative. Mother had similar syndrome, with painful walking, and had a stroke at 37. Patient's alpha Gal A was deficient, leading to diagnosis.
Other features
Dolichoectasia of cerebral vessels
TIA
Vertigo
Hearing loss
Tinnitus
Cognitive disorders
Small fiber neuropathy
Painful acroparesthesias
Hypohidrosis
Impaired temperature sensation
Intestinal dysmotility
Cardiomyopathy
Cardiac conduction abnormality
Renal failure
Angiokeratomas
Corneal dystrophy
Feathery opacities
Autoantibodies in MG
Autoantibodies in thymoma-associated myasthenia gravis with myositis or neuromyotonia.
Thymomas are associated with red cell aplasia and in 50 %, with MG. Some patients with MG have inflammatory myopathy of striated and cardiac muscle. Diagnosis is with prosimal muscle weakness, high CPK levels, and myopathic EMG. Cardiac myositis leads to CHF, arrythmia, and sudden death. Patients with thymoma also may have neuromyotonia (NMT) with hyperactive peripheral motor nerves, myokymia, muscle stiffness, cramps, hypertrophy. EMG shows bursts of high frequency motor unit discharges. Antibodies against VGKC have been detected in NMT with or without thymoma. Other antibodies seen are against skeletal muscle calcium release channel (ryanodine receptor RyR) of sarcoplasmic reticulum; and antibodies to cytoplasmic filaments titin or neurofilaments.
There are 3 subgroups of thymoma associated MG with different spectrum of antibodies. 19/19 had AchR antibodies and 17/19 had anti-titin antibodies that did not correlate with symptoms (although anti-titin was higher in patients with antiRyR). Antititin is more or less synonymous with striated muscle antibodies and correlates with the presence of a thymoma.
10/19 had anti RyR, of which five had myositis and 1 had NMT. Myositis is associated with a poorer prognosis, occassionally rippling muscle disease, electrically silent muscle contractions.
7/16 patients tested had anti VGKC, and 4 had NMT, 1 myositis and 2 nothing. RyR and VGKC coexisted only in 2 patients.
Thymic pathology was not correlated, and included thymic ca and carcinoid.
Thymomas are associated with red cell aplasia and in 50 %, with MG. Some patients with MG have inflammatory myopathy of striated and cardiac muscle. Diagnosis is with prosimal muscle weakness, high CPK levels, and myopathic EMG. Cardiac myositis leads to CHF, arrythmia, and sudden death. Patients with thymoma also may have neuromyotonia (NMT) with hyperactive peripheral motor nerves, myokymia, muscle stiffness, cramps, hypertrophy. EMG shows bursts of high frequency motor unit discharges. Antibodies against VGKC have been detected in NMT with or without thymoma. Other antibodies seen are against skeletal muscle calcium release channel (ryanodine receptor RyR) of sarcoplasmic reticulum; and antibodies to cytoplasmic filaments titin or neurofilaments.
There are 3 subgroups of thymoma associated MG with different spectrum of antibodies. 19/19 had AchR antibodies and 17/19 had anti-titin antibodies that did not correlate with symptoms (although anti-titin was higher in patients with antiRyR). Antititin is more or less synonymous with striated muscle antibodies and correlates with the presence of a thymoma.
10/19 had anti RyR, of which five had myositis and 1 had NMT. Myositis is associated with a poorer prognosis, occassionally rippling muscle disease, electrically silent muscle contractions.
7/16 patients tested had anti VGKC, and 4 had NMT, 1 myositis and 2 nothing. RyR and VGKC coexisted only in 2 patients.
Thymic pathology was not correlated, and included thymic ca and carcinoid.
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