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|Year : 2019 | Volume
| Issue : 6 | Page : 1568-1570
An Adult Presentation of Leigh's Disease-like with Brainstem Involvement
Gaurav K Mittal1, Sachin Sureshbabu1, Sudhir Peter2, Chindripu Sobhana2, Amit Garg3, Raghunath Babu1, Laxmi Khanna1
1 Department of Neurology, St Stephen's Hospital, Tis Hazari, New Delhi, India
2 Department of Pathology, Metropolis Labs, Ernakulum, Kerala, India
3 Department of Radiodiagnosis, St Stephen's Hospital, Tis Hazari, New Delhi, India
|Date of Web Publication||20-Dec-2019|
Dr. Sachin Sureshbabu
Department of Neurology, St Stephen's Hospital, Tis Hazari, New Delhi
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Mittal GK, Sureshbabu S, Peter S, Sobhana C, Garg A, Babu R, Khanna L. An Adult Presentation of Leigh's Disease-like with Brainstem Involvement. Neurol India 2019;67:1568-70
|How to cite this URL:|
Mittal GK, Sureshbabu S, Peter S, Sobhana C, Garg A, Babu R, Khanna L. An Adult Presentation of Leigh's Disease-like with Brainstem Involvement. Neurol India [serial online] 2019 [cited 2020 Jul 12];67:1568-70. Available from: http://www.neurologyindia.com/text.asp?2019/67/6/1568/273650
Leigh's disease is a rare devastating neurometabolic disease first described by the British psychiatrist Denis Archibald Leigh in 1951. A clinical picture of progressive cognitive, oculomotor, and motor deficits coupled with the typical radiological picture of symmetrical basal ganglionic and/or brainstem hyperintensities unveils the diagnosis in most cases. Leigh's disease more commonly affects infants and children whereas adult-onset cases are extremely rare. The typical clinical and radiological presentation is discussed here through the account of a 24-year-old man admitted for evaluation of subacute-onset progressive neurological syndrome localized primarily to the brainstem.
A 24-year-old unemployed youth from the rural part of Northern India was admitted for evaluation of subacute-onset bilateral ophthalmoplegia and encephalopathy of 1-month duration. He was apparently well until a month ago when he developed progressive drooping of both eyelids along with restriction of eye movements and diplopia. Fluctuations, diurnal variations, or fatigue were not reported. One week into the illness, progressively withdrawn behavior was observed by the family along with reduced and at times incoherent conversation. Swallowing difficulty with occasional choking, clumsy motor performance, and unsteady gait were other symptoms which emerged around the same time. Deterioration of neurological status was evident for the week after which the symptomatology remained relatively static. Fever, seizures, headache, arthralgias, oral, genital ulcers, photosensitivity, drug or substance abuse, exposure to toxins or medications, contact with animals, recent travel, dog bite, vaccination, sexual promiscuity, and family history of neurological illness and consanguinity were ruled out after interrogation of friends and family.
On examination, he was disoriented, with poor attention and dysarthric speech. Visual acuity and fundus examination were normal. Pupils were mid-dilated and poorly reacting. There was bilateral ptosis with complete restriction of all eye movements except for abduction in the right eye. These findings were consistent with One and Half syndrome. Palatal excursions were symmetrical but bilaterally diminished along with an attenuated gag response. Tone was increased in all four limbs with grade 4+/5 motor power and exaggerated reflexes. Upper limb incoordination, dysmetria, heel shin incoordination, and gait ataxia were also observed. Sensory evaluation was inconclusive due to inconsistent responses and poor cooperation from the patient. Blood work including complete blood count, liver and renal functions, lipid profile, and uric acid was normal. Vasculitic panel and serological assay for anti-GQ1 B antibodies were negative. Chest Skiagram, ultrasound abdomen, electrocardiogram, and a two-dimensional echocardiogram were normal.
Magnetic resonance imaging (MRI) of the brain revealed T2 and fluid attenuated inversion recovery (FLAIR) symmetrical hyperintensities in bilateral symmetrical hyperintensities in tectum and tegmentum of midbrain, extending caudally into dorsal pons and both superior cerebellar peduncles [Figure 1]. No enhancement was noted after gadolinium administration; neither was any restriction evident on diffusion-weighted imaging (DWI). Magnetic resonance spectroscopy (MRS) of the lesion showed a large lactate peak [Figure 2]. Arterial blood gas (ABG) and cerebrospinal fluid (CSF) lactate levels were in the normal range. CSF protein was 28 mg/dL with no cells and normal sugar. Virological panel for neurotropic viruses (including HHV-6 and EBV), gram stain and culture, as well as autoimmune/paraneoplastic encephalitis panel were negative. EEG showed bilateral symmetrical slowing in the range of 5–6 Hz with no epileptiform discharges. Nerve conduction study revealed motor axonal neuropathy in lower limbs and diffuse sensory axonal neuropathy. Intravenous pulse methylprednisolone was initiated on day 1 empirically along with antibiotics and acyclovir for broad-spectrum coverage of the many differentials of rhomboencephalitis. The clinical and radiological features were most consistent with a Leigh-like syndrome. Therefore, in addition, a cocktail therapy for mitochondrial disorders was initiated comprising intravenous thiamine, coenzyme-Q, riboflavin, L-carnitine, and L-arginine. After a week of admission, no significant response to therapy was apparent.
|Figure 1: 1.5 Tesla MRI T of brain show apparently normal findings on T1 (a) and bilateral symmetrical hyperintensities in tectum and tegmentum of midbrain (b and c respectively)|
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|Figure 2: Proton MR Spectroscopy (long TE 144) of the left half of midbrain showed a large lactate peak|
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| » Discussion|| |
Leigh's syndrome is an extremely rare neurometabolic disorder typically seen in the first year(s) of life usually with rapid clinical deterioration, though clinical heterogeneity has been frequently reported. The mitochondrial enzymes implicated are pyruvate carboxylase, pyruvate dehydrogenase, cytochrome C oxidase, and Complex 1 (NAD-Coenzyme Q Reductase) deficiencies., In addition, variegate mutations of several genes like SURF – 1 that are involved in the assembly and integrity of the cytochrome oxidase complex can result in this potentially fatal encephalopathy. Decompensation usually follows an acute intercurrent illness.
Rehman et al. proposed four mandatory requirements for diagnosis: (1) progressive neurologic disease with motor and intellectual developmental delay; (2) signs and symptoms of brainstem and/or basal ganglia disease; (3) raised lactate concentration in blood and/or CSF (4) one or more of the following: (a) characteristic features on neuroimaging with symmetrical hyperintense lesions in the basal ganglia and or brainstem on a T2 sequence. (b) characteristic neuropathological changes include spongiform lesions with relative preservation of neurons, demyelination and gliosis. The areas involved include the thalamus, brain stem, cerebellum, basal ganglia and optic nerves. (c) similar neuropathological changes in affected siblings.
Recently, Baertling et al. described a less stringent diagnostic criteria that allow the diagnosis of Leigh's syndrome in the absence of raised lactate levels. Their criteria included the following:
- Neurodegenerative disease with variable symptoms resulting from mitochondrial dysfunction
- Mitochondrial dysfunction caused by a hereditary genetic defect
- Bilateral central nervous system lesions that can be associated with further abnormalities on diagnostic imaging.
To accommodate the broader spectrum of this illness, the concept of “Leigh-like syndrome” was introduced. The term describes the outliers where either the neuropathology, imaging, or lactate levels were not typical of the disease, but the overall clinical and radiological picture were concordant.
Our patient had clinical features suggestive of Leigh's syndrome such as a progressive neurological disease with motor impairment and signs and symptoms of brainstem involvement. Neuroimaging also revealed typical features such as bilateral symmetrical hyperintensities in the tectum and tegmentum of midbrain extending caudally into the dorsal pons and both superior cerebellar peduncles with additional evidence in the form of a lactate peak on MRS. The normal levels of lactate in blood and CSF, however, confined the diagnosis to Leighs-like syndrome.
Widespread availability of MRI has enabled recognition of more patients with LS, especially in the early phase of illness. In addition, MRS provides a window into thebiochemical state of a variety of brain compounds, which further helps to identify the physiopathology of brain lesions in metabolic diseases. Lactate elevations in the anatomical substrates occur during clinical exacerbations which can be easily captured by this imaging tool.
This case illustrates the classical clinicoradiological pattern of a neurological insult largely restricted to the brainstem. The differentials entertained in such a presentation would fall into four broad categories: (1) Infections – Listeria, Enteroviruses, Flaviviruses, etc.; (2) autoimmune – Behcet's disease, Systemic lupus erythematosus, Sjogren's syndrome, sarcoidosis; (3) neoplastic/paraneoplastic-lymphoma, anti-Ma encephalitis; (4) neurometabolic/genetic – Leigh's, Wernicke encephalopathy, etc. The absence of systemic signs and symptoms, fever, or meningeal irritation and a normal lumbar tap argues against the first three possibilities. However, a complete workup was undertaken to obviate the omission of indolent presentations. The other clinical pointer in favor of the neurometabolic origin of findings was the perfect symmetry of imaging abnormalities further supplemented by the lactate peak on MRS.
| » Conclusion|| |
We report this case of Leigh-like syndrome with onset at the age of 24 years with normal serum lactate but typical MRI and MRS findings. Because of the wide heterogeneity in the clinical presentation as well as diagnostic uncertainties in Leigh's syndrome, it becomes extremely difficult at times for neurologists to reach at a conclusive diagnosis. By presenting this case we want to highlight the adult-onset form of Leigh's disease, as well as the use of MRS in diagnosing this rare entity.
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Conflicts of interest
There are no conflicts of interest.
| » References|| |
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[Figure 1], [Figure 2]