In This Case Study
- A 55-year-old male patient with a history of alcohol use disorder and hepatic steatosis presented with three weeks of numbness, paresthesia and pain involving his bilateral upper and lower extremities and face
- Exam was notable for severe discomfort to tactile stimulation of his bilateral distal extremities, absent reflexes, markedly decreased proprioception, severe sensory ataxia, and decreased sensation across all modalities
- The Pathways Consult Service in the Department of Medicine at Massachusetts General Hospital was engaged to better understand the cause of the patient's symptoms
A 55-year-old male patient with a history of alcohol use disorder and hepatic steatosis presented with three weeks of numbness, paresthesia and pain involving his bilateral upper and lower extremities and face. The exam was notable for severe discomfort to tactile stimulation of his bilateral distal extremities, absent reflexes, markedly decreased proprioception, severe sensory ataxia, and decreased sensation across all modalities (i.e., vibration, light touch, temperature and pinprick). Broad infectious workup proved negative. His hospital course was notable for ileus (lack of normal muscle contractions in the intestines), persistent tachycardia, as well as waxing and waning encephalopathy. Laboratory work-up revealed several findings of questionable significance including mild deficiencies of vitamins B6 and B12, folate, low normal vitamin E, elevated cadmium level on the heavy metal screen, elevated iron saturation, and hereditary hemochromatosis gene (HFE gene) H63D mutation. His nutritional (folate, B12, and presumed thiamine) deficiencies were treated. Two weeks into his admission, he was started on a 5-day course of intravenous immune globulin as empiric treatment for an autoimmune/paraneoplastic etiology.
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With minimal improvement of symptoms three weeks post-admission, the Pathways Consult Service in the Department of Medicine at Massachusetts General Hospital was engaged to better understand the cause of the patient's symptoms. Nerve conduction studies indicated a generalized non-length-dependent sensory neuropathy with normal motor conduction, consistent with a sensory ganglionopathy. The Pathways Consult Service focused on the mechanism contributing to our patient's sensory ganglionopathy through two potential pathways:
- Decompensation from an existing metabolic deficiency
Background and Diagnosis
Sensory ganglia contain cell bodies of sensory nerves that run along the spinal cord and are joined at the dorsal roots. The sensory nerves then project to the periphery, enabling input from the senses. Sensory ganglionopathy is characterized by loss of sensory input in the absence of weakness. Types and causes of sensory ganglionopathy include systemic autoimmune (e.g., Sjogren's disease), paraneoplastic (e.g., small-cell lung cancer), infection, drug/toxicity and idiopathic (N Engl J Med). Sjogren's disease can present with isolated sensory ganglionopathy, even in absence of overt sicca symptoms (dry mouth and dry eyes) or positive serology (Ann Neurol). Over half of sensory ganglionopathies end up being classified as idiopathic without elucidation of a disease-causing mechanism.
Our patient presented with severe dysfunction of sensory neurons whose cell bodies reside in the dorsal root and trigeminal ganglia, as well as evidence of dysfunction of post-ganglionic autonomic neurons. Given the common developmental origin of these entities in the neural crest and the vulnerable location of the cell bodies for these neurons outside the blood-CNS and blood-neuron barriers, it is possible that immune-mediated (autoimmune or paraneoplastic) targeting of a shared molecular epitope may underlie his presentation. Autopsy and biopsy in Sjogren's patients have revealed CD8+ T cell infiltration of the dorsal root ganglion, although the targeted epitopes remain unknown (Ann Neurol, J Neurol Sci). While some paraneoplastic syndromes involve autoantibodies, many paraneoplastic ganglionopathies are also thought mediated by cytotoxic T cells reactive against sensory neuron antigens.
Immune-mediated ganglionopathy may also be facilitated by autoreactive antibodies. Indeed, anti-fibroblast growth factor receptor 3 (FGFR3) antibodies have recently been associated with over 10% of patients with unexplained sensory ganglionopathy (J Neurol Neurosurg Psychiatry, J Neurol Neurosurg Psychiatry). FGFR3 plays a role in neuronal differentiation, migration, synaptogenesis, and response to injury (Neuron). Anti-FGFR3 antibodies could therefore play a pathogenic role through modulating FGFR3 signaling or initiating immune-mediated damage of sensory neurons. Alternatively, they may be bystander disease markers reflecting antigen exposure during neuronal injury. Similarly, trisulfated heparin disaccharide (THD) antibodies have been reported enriched in those with sensory ganglionopathy, but whether they play a mechanistic role is unknown (Muscle Nerve). It is possible that our patient's immune-targeted neuronal epitope may be yet uncharacterized, warranting the employment of novel methodologies to identify unknown autoreactive T cell and autoantibody antigens.
The second focus of our investigation was on the contribution of metabolic dysfunction to the development of ganglionopathy. Friedreich's ataxia (FA) is an autosomal recessive disorder caused by the expansion of GAA trinucleotide repeats in FXN, which encodes frataxin, a protein involved in iron-sulfur cluster assembly. FA classically presents in childhood with sensory neuropathy, ataxia and loss of reflexes. Presentation of FA in adulthood can occur, with disease onset typically beginning in the dorsal root ganglia. Progressive age-dependent GAA gene expansion in FA is disproportionally pronounced in the dorsal root ganglia compared to other parts of the nervous system (Ann Neurol). Evidence supports an abnormal local accumulation of iron in satellite cells around afflicted neurons in FA (Methods Mol Biol).
Given the believed role of oxidant susceptibility in mediating the phenotype of frataxin loss, it is possible that our patient presents with acute decompensation of late-onset FA due to severe oxidative stress induced by the confluence of iron overload facilitated by HFE mutation, oxidant stress imposed by cadmium toxicity and homocysteinemia, and hindered antioxidant protection due to low vitamin E and B vitamin deficiencies (Curr Opin Physiol). Like acute intermittent porphyria, where a deficiency in an enzyme in the heme synthesis pathway can silently exist for decades before presenting acutely, we propose that our patient may harbor a previously compensated genetic deficiency in a metabolic enzyme that has been tipped into acute decompensation by one or more of his presenting toxic-metabolic stresses.
Summary and Future Steps
We propose that our patient had sensory ganglionopathy (dorsal root ganglionopathy, trigeminal ganglionopathy) with possible autonomic involvement through either an immune-mediated neuronal injury or decompensation of an existing metabolic deficiency. To understand the cause of sensory ganglionopathy, a panel of examinations is warranted. This includes FGFR3 and THD antibody testing, assessing for Sjogren's disease, unbiased profiling of auto-antibodies and T cells, and FA frataxin trinucleotide repeat expansion assay. Together, these assays may provide insight into the underlying mechanisms of sensory ganglionopathy, leading to improved treatment strategies for our patient and future patients with this disabling syndrome.
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