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Problems with Botulinum Toxin Treatment in Mitochondrial Cytopathy

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Problems with Botulinum Toxin Treatment in Mitochondrial Cytopathy 1594 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.057661 on 14 October 2005. Downloaded from SHORT REPORT Problems with botulinum toxin treatment in mitochondrial cytopathy: case report and review of the literature T Gioltzoglou, C Cordivari, P J Lee, M G Hanna, A J Lees ............................................................................................................................... J Neurol Neurosurg Psychiatry 2005;76:1594–1596. doi: 10.1136/jnnp.2004.057661 We report two patients (a brother and sister) who had an Botulinum toxin type A (BTXA) is widely used in neurological unexpected reaction to botulinum toxin injections into their therapeutics for a variety of indications such as dystonia, parotid and submandibular glands for the treatment of spasticity, hyperhidrosis, and hypersalivation. It is relatively sialorrhoea. contraindicated in disorders of neuromuscular transmission, in individuals with known hypersensitivity or bleeding CASE REPORTS disorders, and during pregnancy. Two patients are presented Patient 1 with initially undetermined multisystem neurological disor- The first patient was a 30 year old man with an insidious ders and excessive sialorrhoea, later diagnosed as mito- onset of intellectual and movement disorders in infancy. He chondrial cytopathy, who had side effects after treatment had delayed motor and intellectual development. He was with ultrasound guided BTXA injections. Published reports on wheelchair bounded, while his language was limited to single the use of BTXA injections in hypersalivation of various words or simple phrases. He had good comprehension and causes are reviewed, along with the proposed mechanisms of memory, and normal sphincter function. He had no difficulty hypersensitivity to BTXA in patients with mitochondrial in swallowing. cytopathies. Clinicians should be cautious when using BTXA Neurologically, multiple systems were affected, resulting in injections in such patients because of the significant risk of spasticity, pigmentary changes in both eyes on fundoscopy, side effects. marked startle response, intention tremor (improved on CoQ10), right foot dystonia, variable dyskinesias of the neck, trunk, and arms, and hypersalivation. His full blood count, erythrocyte sedimentation rate, urea and electrolytes, liver copyright. otulinum toxin type A (BTXA) is widely used in function tests, C reactive protein, coagulation screen, vitamin neurological therapeutics for indications as varied as B-12, thyroid function tests, antinuclear antibody screen, focal dystonia, spasticity, hemifacial spasm, hyperhidro- B protein electrophoretic strip, a-fetoprotein, glucose, folate, sis, and drooling of saliva. It acts by inhibiting acetylcholine acanthocytes, and vitamin E were normal. Plasma lactate was release from nerve terminals, producing muscle paralysis. It normal. His white cell enzymes and very long fatty acids were does this by disrupting exocytosis at the nerve ending. normal. Copper studies (Cu and caeruloplasmin) were Exocytosis requires the interaction of multiple proteins that normal. Genetic testing for spinocerebellar ataxias, DYT-1, are embedded in the vesicle, the cytosol, and the nerve Huntington’s disease, dentatorubropallidoluysian atrophy, terminal membrane. These proteins are responsible for the and Freidreich’s ataxia was negative. Cranial MRI showed attachment of the vesicle to the presynaptic membrane to volume loss of cerebellum and brain stem. facilitate exocytosis. BTXA cleaves SNAP-25, a cytosolic Electroencephalography, electromyography, and nerve con- protein attached to the presynaptic membrane. The dosage duction studies were normal. http://jnnp.bmj.com/ used clinically reduces but does not completely block In December 2002 the patient received botulinum toxin A neuromuscular transmission.12 (DysportH) injections as follows: 120 mU in each parotid BTXA is relatively contraindicated in the following gland for excessive drooling, 100 mU into the right tibialis circumstances: anterior muscle and 200 mU into the right tibialis posterior N in individuals with a known hypersensitivity to any muscle for right foot inturning. There was moderate component of the formulation; reduction of saliva secretion and mild muscle relaxation of the right leg. At this stage there were no side effects. The N when there are disorders of neuromuscular transmission benefit lasted for about two months. on September 30, 2021 by guest. Protected (such as myasthenia gravis); When the effect started to wear off he had further N when aminoglycoside antibiotics or streptomycin are injections, by the same physician, of 120 mU Dysport in already used or are likely to be used; each parotid gland and 60 mU in each submandibular gland N when there are bleeding disorders of any type, antic- under ultrasound guidance. He also received 300 mU of oagulant therapy, or any reason to avoid intramuscular Dysport in the right tibialis anterior muscle and 100 mU in injections; the right tibialis posterior muscle. Ten days after this second N during pregnancy. course of injections the patient started having difficulty in swallowing. He was admitted to hospital for 10 days, needing There are also isolated case reports describing repeated a nasogastric tube. He improved, but required a fluid diet. specific problems: marked ptosis in a patient with mito- The dysphagia had a fluctuating course necessitating a chondrial cytopathy and blepharospasm treated with botuli- nasogastric tube from time to time. One month after the num toxin injection; general weakness in a patient with onset of dysphagia the patient had an episode of pneumonia. amyotrophic lateral sclerosis (ALS) after focal botulinum He never had fatigue. Dysphagia subsided completely two toxin injection; and severe and prolonged dysphagia complicating BTXA injections for dystonia in Machado– Abbreviations: ALS, amyotrophic lateral sclerosis; BTXA, botulinum Joseph disease.3–5 toxin type A www.jnnp.com Botulinum toxin therapy in mitochondrial cytopathy 1595 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2004.057661 on 14 October 2005. Downloaded from months after the second course of injections. A repetitive of the mitochondrial respiratory chain. In the absence of nerve stimulation test in the proximal and distal muscles any other defects, and in view of the enzymology and (accessory, axillary, and ulnar nerves) of his right upper limb clinical picture, we believe these siblings have a primary showed no significant compound muscle action potential mitochondrial disorder. The total dose of Dysport did not decrement. Single fibre electromyography of the orbicularis exceed the suggested maximum dose in either of them, oculi and extensor carpi radialis muscles showed normal neither were they underweight (brother 82 kg, sister muscle fibre jitter and no blocks. 56 kg), and the injections were ultrasound guided. Results of a muscle biopsy carried out a few days before the Unfortunately they both developed side effects, which we botulinum toxin treatment showed muscle fibres containing believe reflected a vulnerability to BTXA because of their mitochondria with disrupted internal architecture and mitochondrial cytopathy, because the same doses used in whorled membranous material within them. Mitochondrial other patients with sialorrhoea secondary to Parkinson’s respiratory chain enzymes suggested complex II/III defi- disease or stroke have not caused such problems. However, ciency, as follows: although our patients never had difficulty in swallowing NADH ubiquinone reductase, 0.141 (normal, 0.104 to before, we cannot entirely rule out the possibility that they 0.268); succinate cytochrome C reductase, 0.019 (0.040 to had subclinical dysphagia owing to brain stem and cerebellar 0.204); cytochrome oxidase, 0.014 (0.014 to 0.34). involvement. Dysphagia after injections of botulinum toxin result from Patient 2 weakness of the swallowing musculature caused by local The second patient was the first patient’s 32 year old sister. toxin diffusion.5 Other proposed mechanisms include sys- There was a normal pregnancy and a normal neonatal course. temic distribution by blood flow19 and retrograde axonal She had delayed motor and intellectual development. She sat transport to the ipsilateral spinal anterior horn cells, alone at 9 to 10 months, crawled at one year, and did not following anterograde transport through the respective walk until 18 months. She never developed speech, but was axon.19 20 Patients who already suffer from diseases of the able to recognise some words. The neurological features of neuromuscular junction are extremely sensitive to botulinum her disorder included spasticity, tremor, and mental retarda- toxin, and myasthenia gravis and Lambert–Eaton syndrome tion. Her neurological condition was very similar to that of are contraindications for its use. Subclinical Lambert–Eaton her brother, as was her cranial MRI. syndrome can even be unmasked after local botulinum toxin As her main problem was excessive drooling she was injections.21 Patients with anterior horn cell disorders, such as treated for the first time with botulinum toxin injections (120 ALS or Machado–Joseph disease, are also reported to have mU of Dysport in each parotid gland and 50 mU in each hypersensitivity to botulinum toxin.45 submandibular gland under ultrasound guidance) at the time In addition to our cases, there is a report describing marked when her brother had his second course of injections. Her bilateral ptosis, weakness
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